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Sphingosine Kinase Mediates Vascular Endothelial Growth Factor-Induced Activation of Ras and Mitogen-Activated Protein Kinases
Xiaodong Shu, Weicheng Wu, Raymond D. Mosteller, and Daniel Broek*
Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine at the University of Southern California, Los Angeles, California 90089
Received for publication 4 March 2002.
Revision received 17 April 2002.
Accepted for publication 22 August 2002.
Abstract:
Vascular endothelial growth factor (VEGF) signaling is criticalto the processes of angiogenesis and tumor growth. Here, evidenceis presented for VEGF stimulation of sphingosine kinase (SPK)that affects not only endothelial cell signaling but also tumorcells expressing VEGF receptors. VEGF or phorbol 12-myristate13-acetate treatment of the T24 bladder tumor cell line resultedin a time- and dose-dependent stimulation of SPK activity. InT24 cells, VEGF treatment reduced cellular sphingosine levelswhile raising that of sphingosine-1-phosphate. VEGF stimulationof T24 cells caused a slow and sustained accumulation of Ras-GTPand phosphorylated extracellular signal-regulated kinase (phospho-ERK)compared with that after EGF treatment. Small interfering RNA(siRNA) that targets SPK1, but not SPK2, blocks VEGF-inducedaccumulation of Ras-GTP and phospho-ERK in T24 cells. In contrastto EGF stimulation, VEGF stimulation of ERK1/2 phosphorylationwas unaffected by dominant-negative Ras-N17. Raf kinase inhibitionblocked both VEGF- and EGF-stimulated accumulation of phospho-ERK1/2.Inhibition of SPK by pharmacological inhibitors, a dominant-negativeSPK mutant, or siRNA that targets SPK blocked VEGF, but notEGF, induction of phospho-ERK1/2. We conclude that VEGF inducesDNA synthesis in a pathway which sequentially involves proteinkinase C (PKC), SPK, Ras, Raf, and ERK1/2. These data highlighta novel mechanism by which SPK mediates signaling from PKC toRas in a manner independent of Ras-guanine nucleotide exchangefactor.
* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine at the University of Southern California, Los Angeles, CA 90089. Phone: (323) 856-0523. Fax: (323) 865-0154. E-mail: broek{at}usc.edu.
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