Stereospecificity of sphingosine-induced intracellular calcium mobilization and cellular proliferation.
Sphingosine is a positive regulator of cell growth in Swiss 3T3 fibroblasts (Zhang, H., Buckley, N. E., Gibson, K., and Spiegel, S. (1990) J. Biol. Chem. 265, 76-81). The present study investigated the stereospecificity of sphingosine-induced cell proliferation and its mitogenic signal transduction mechanisms. D-(+)-erythro Stereoisomers (cis and trans) stimulated DNA synthesis, whereas neither L-(-)-threo-sphingosine (cis or trans) nor DL-threo-dihydrosphingosine had any effect. Previously, we have shown that sphingosine-1-phosphate may mediate the mitogenic effect of sphingosine (Zhang, H., Desai, N. N., Olivera, A., Seki, T., Brooker, G., and Spiegel, S. (1991) J. Cell Biol. 114, 155-167). However, no major differences were found in the formation of D-(+)-erythro- and L-(-)-threo- sphingosine-1-phosphate derived from the respective sphingosine isomers in intact cells. Thus, the stereospecificity of the response to sphingosine may reside at the level of specific intracellular targets for sphingosine-1-phosphate. Sphingosine-1-phosphate triggers dual signal transduction pathways of activation of phospholipase D leading to increases in the levels of phosphatidic acid and mobilization of calcium from internal stores. Both D-(+)-erythro- and L-(-)-threo-sphingosine isomers induced similar increases in phosphatidic acid concomitant with identical decreases in phosphatidylcholine levels. In contrast, only the D-(+)-erythro-stereoisomers (cis and trans) were effective in releasing calcium from intracellular stores. Our results suggest that the formation of phosphatidic acid is not sufficient to mediate sphingosine-stimulated DNA synthesis. However, the stereospecificity of the sphingosine-induced mobilization of calcium from internal stores seems to correlate with the induction of DNA synthesis by sphingosine stereoisomers.
Olivera
A
A
Department of Biochemistry and Molecular Biology, Georgetown University Medical Center, Washington, D.C. 20007.
Zhang
H
H
Carlson
R O
RO
Mattie
M E
ME
Schmidt
R R
RR
Spiegel
S
S
D016475:3T3 Cells; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002455:Cell Division / Q000502:physiology*; D051379:Mice; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D015398:Signal Transduction; D013110:Sphingosine / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013379:Substrate Specificity; D000099157:Sphingosine Kinase
D002118:Calcium; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; D000099157:Sphingosine Kinase