Tumor necrosis factor-alpha induces stress fiber formation through ceramide production: role of sphingosine kinase
| Autor: | Yutaka Kikuchi, Atef N. Hanna, David N. Brindley, Luc G. Berthiaume, David A. Begg, Sylvain G. Bourgoin |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
Ceramide
Sphingosine kinase Sphingomyelin phosphodiesterase Biology Article Proinflammatory cytokine Cell Line chemistry.chemical_compound Sphingosine Stress Fibers Animals Humans ASK1 Phosphorylation cdc42 GTP-Binding Protein Molecular Biology Cytoskeleton Tumor Necrosis Factor-alpha Cell Biology Lipid signaling Protein-Tyrosine Kinases Phosphoproteins Cell biology Rats rac GTP-Binding Proteins Cytoskeletal Proteins Phosphotransferases (Alcohol Group Acceptor) Sphingomyelin Phosphodiesterase chemistry Focal Adhesion Kinase 1 Focal Adhesion Protein-Tyrosine Kinases Second messenger system Cancer research ras Proteins Tyrosine Paxillin rhoA GTP-Binding Protein |
| Zdroj: | Molecular biology of the cell. 12(11) |
| ISSN: | 1059-1524 |
| Popis: | Tumor necrosis factor-α (TNF-α) is a proinflammatory cytokine that activates several signaling cascades. We determined the extent to which ceramide is a second messenger for TNF-α-induced signaling leading to cytoskeletal rearrangement in Rat2 fibroblasts. TNF-α, sphingomyelinase, or C2-ceramide induced tyrosine phosphorylation of focal adhesion kinase (FAK) and paxillin, and stress fiber formation. Ly 294002, a phosphatidylinositol 3-kinase (PI 3-K) inhibitor, or expression of dominant/negative Ras (N17) completely blocked C2-ceramide- and sphingomyelinase-induced tyrosine phosphorylation of FAK and paxillin and severely decreased stress fiber formation. The TNF-α effects were only partially inhibited. Dimethylsphingosine, a sphingosine kinase (SK) inhibitor, blocked stress fiber formation by TNF-α and C2-ceramide. TNF-α, sphingomyelinase, and C2-ceramide translocated Cdc42, Rac, and RhoA to membranes, and stimulated p21-activated protein kinase downstream of Ras-GTP, PI 3-K, and SK. Transfection with inactive RhoA inhibited the TNF-α- and C2-ceramide-induced stress fiber formation. Our results demonstrate that stimulation by TNF-α, which increases sphingomyelinase activity and ceramide formation, activates sphingosine kinase, Rho family GTPases, focal adhesion kinase, and paxillin. This novel pathway of ceramide signaling can account for ∼70% of TNF-α-induced stress fiber formation and cytoskeletal reorganization. |
| Databáze: | OpenAIRE |
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