+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

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



Molecular and Cellular Biology 20(24): 9247-9261



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.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 010853709

Download citation: RISBibTeXText

PMID: 11094076

DOI: 10.1128/mcb.20.24.9247-9261.2000


Related references

Sphingosine 1-phosphate-induced cell proliferation, survival, and related signaling events mediated by G protein-coupled receptors Edg3 and Edg5. Journal of Biological Chemistry 275(1): 288-296, 2000

Molecular regulation of the angiogenic sphingosine-1-phosphate receptors S1P1/EDG1 and S1P3/EDG3. International Journal of Molecular Medicine 10(Suppl. 1): S81, 2002

EDG3 is a functional receptor specific for sphingosine 1-phosphate and sphingosylphosphorylcholine with signaling characteristics distinct from EDG1 and AGR16. Biochemical and Biophysical Research Communications 260(1): 203-208, 1999

Sphingosine 1-phosphate inhibits DNA synthesis induced by growth factors in cultured rat hepatocytes with activation of the small GTPase Rho via G protein-coupled receptor, EDG5. Hepatology 34(4 Pt 2): 387A, 2001

Sphingosine 1-phosphate evokes calcium signals in C2C12 myoblasts via Edg3 and Edg5 receptors. Biochemical Journal 362(Pt 2): 349-357, 2002

Molecular mechanisms of sphingosine-1-phosphate receptor S1P2/Edg5-mediated inhibition of Rac and cell migration. Seikagaku. Journal of Japanese Biochemical Society 75(7): 597-600, 2003

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. Molecular and Cellular Biology 23(5): 1534-1545, 2003

Dual regulation of EDG1 receptor phosphorylation and internalisation by sphingosine-1-phosphate and protein kinase C is controlled by its carboxyl terminus. Biochemical Society Transactions 29(3): A83, 2001

EDG1 is a functional sphingosine-1-phosphate receptor that is linked via a Gi/o to multiple signaling pathways, including phospholipase C activation, Ca2+ mobilization, Ras-mitogen-activated protein kinase activation, and adenylate cyclase inhibition. Journal of Biological Chemistry 273(42): 27104-27110, 1998

Activation of a high affinity G-i protein-coupled plasma membrane receptor by sphingosine-1-phosphate. Journal of Biological Chemistry 271(4): 2082-2087, 1996

Regulation of the roles of sphingosine 1-phosphate and its type 1 G protein-coupled receptor in T cell immunity and autoimmunity. Biochimica et Biophysica Acta 1781(9): 503-507, 2008

Type 4 sphingosine 1-phosphate G protein-coupled receptor (S1P4) transduces S1P effects on T cell proliferation and cytokine secretion without signaling migration. Faseb Journal 19(12): 1731-1733, 2005