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.
Department of Biochemistry and Molecular Biology, Georgetown University Medical Center, Washington, D.C. 20007.
A
A
Olivera
H
H
Zhang
R O
RO
Carlson
M E
ME
Mattie
R R
RR
Schmidt
S
S
Spiegel
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