Sphingosine kinase mediates vascular endothelial growth factor-induced activation of ras and mitogen-activated protein kinases
| Autor: | Weicheng Wu, Xiaodong Shu, Daniel Broek, Raymond D. Mosteller |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
Vascular Endothelial Growth Factor A
Angiogenesis MAP Kinase Signaling System Sphingosine kinase Endothelial Growth Factors Biology chemistry.chemical_compound Tumor Cells Cultured Humans Enzyme Inhibitors Molecular Biology Cell Growth and Development Protein kinase C Protein Kinase C Lymphokines Sphingosine Kinase Vascular Endothelial Growth Factors Carcinoma Cell Biology Cell biology Vascular endothelial growth factor Endothelial stem cell Enzyme Activation Vascular endothelial growth factor A Phosphotransferases (Alcohol Group Acceptor) chemistry Urinary Bladder Neoplasms ras GTPase-Activating Proteins Cancer research Intercellular Signaling Peptides and Proteins Tetradecanoylphorbol Acetate ras Guanine Nucleotide Exchange Factors Endothelium Vascular Mitogen-Activated Protein Kinases |
| Zdroj: | Molecular and cellular biology. 22(22) |
| ISSN: | 0270-7306 |
| Popis: | Vascular endothelial growth factor (VEGF) signaling is critical to the processes of angiogenesis and tumor growth. Here, evidence is presented for VEGF stimulation of sphingosine kinase (SPK) that affects not only endothelial cell signaling but also tumor cells expressing VEGF receptors. VEGF or phorbol 12-myristate 13-acetate treatment of the T24 bladder tumor cell line resulted in a time- and dose-dependent stimulation of SPK activity. In T24 cells, VEGF treatment reduced cellular sphingosine levels while raising that of sphingosine-1-phosphate. VEGF stimulation of T24 cells caused a slow and sustained accumulation of Ras-GTP and 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-induced accumulation of Ras-GTP and phospho-ERK in T24 cells. In contrast to EGF stimulation, VEGF stimulation of ERK1/2 phosphorylation was unaffected by dominant-negative Ras-N17. Raf kinase inhibition blocked both VEGF- and EGF-stimulated accumulation of phospho-ERK1/2. Inhibition of SPK by pharmacological inhibitors, a dominant-negative SPK mutant, or siRNA that targets SPK blocked VEGF, but not EGF, induction of phospho-ERK1/2. We conclude that VEGF induces DNA synthesis in a pathway which sequentially involves protein kinase C (PKC), SPK, Ras, Raf, and ERK1/2. These data highlight a novel mechanism by which SPK mediates signaling from PKC to Ras in a manner independent of Ras-guanine nucleotide exchange factor. |
| Databáze: | OpenAIRE |
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