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(The FASEB Journal. 1999;13:1593-1600.)
© 1999 FASEB

Platelet-derived growth factor-induced activation of sphingosine kinase requires phosphorylation of the PDGF receptor tyrosine residue responsible for binding of PLC{gamma}

ANA OLIVERA, LISA EDSALL, SAMANTHA POULTON, ANDRIUS KAZLAUSKAS* and SARAH SPIEGEL1

Department of Biochemistry and Molecular Biology, Georgetown University Medical Center, Washington, D.C. 20007, USA; and the
* Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts 02114, USA

1Correspondence: Department of Biochemistry and Molecular Biology, Georgetown University Medical Center, 353 Basic Science Building, 3900 Reservoir Road, NW, Washington, DC 20007, USA. E-mail: spiegel{at}bc.georgetown.edu

Sphingosine-1-phosphate, a sphingolipid metabolite, is involved in the mitogenic response of platelet-derived growth factor (PDGF) and is formed by activation of sphingosine kinase. We examined the effect of PDGF on sphingosine kinase activation in TRMP cells expressing wild-type or various mutant ßPDGF receptors. Sphingosine kinase was stimulated by PDGF in cells expressing wild-type receptors but not in cells expressing kinase-inactive receptors (R634). Cells expressing mutated PDGF receptors with phenylalanine substitutions at five major tyrosine phosphorylation sites 740/751/771/1009/1021 (F5 mutants), which are unable to associate with PLC{gamma}, phosphatidylinositol 3-kinase, Ras GTPase-activating protein, or protein tyrosine phosphatase SHP-2, not only failed to increase DNA synthesis in response to PDGF but also did not activate sphingosine kinase. Moreover, mutation of tyrosine-1021 of the PDGF receptor to phenylalanine, which impairs its association with PLC{gamma}, abrogated PDGF-induced activation of sphingosine kinase. In contrast, PDGF was still able to stimulate sphingosine kinase in cells expressing the PDGF receptor mutated at tyrosines 740/751 and 1009, responsible for binding of phosphatidylinositol 3-kinase and SHP-2, respectively. In agreement, PDGF did not stimulate sphingosine kinase activity in F5 receptor `add-back' mutants in which association with the Ras GTPase-activating protein, phosphatidylinositol 3-kinase, or SHP-2 was individually restored. However, a mutant PDGF receptor that was able to bind PLC{gamma} (tyrosine-1021), but not other signaling proteins, restored sphingosine kinase sensitivity to PDGF. These data indicate that the tyrosine residue responsible for binding of PLC{gamma} is required for PDGF-induced activation of sphingosine kinase. Moreover, calcium mobilization downstream of PLC{gamma}, but not protein kinase C activation, appears to be required for stimulation of sphingosine kinase by PDGF.—Olivera, A., Edsall, J., Poulton, S., Kazlauskas, A., Spiegel, S. Platelet-derived growth factor-induced activation of sphingosine kinase requires phosphorylation of the PDGF receptor tyrosine residue responsible for binding of PLC{gamma}.


Key Words: platelet-derived growth factor • SPP • DNA synthesis • DMS




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