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A Novel Pathway for Tumor Necrosis Factor-α and Ceramide Signaling Involving Sequential Activation of Tyrosine Kinase, p21 , and Phosphatidylinositol 3-Kinase
- Source :
- Journal of Biological Chemistry. 274:12722-12729
- Publication Year :
- 1999
- Publisher :
- Elsevier BV, 1999.
-
Abstract
- Treatment of confluent rat2 fibroblasts with C2-ceramide (N-acetylsphingosine), sphingomyelinase, or tumor necrosis factor-alpha (TNFalpha) increased phosphatidylinositol (PI) 3-kinase activity by 3-6-fold after 10 min. This effect of C2-ceramide depended on tyrosine kinase activity and an increase in Ras-GTP levels. Increased PI 3-kinase activity was also accompanied by its translocation to the membrane fraction, increases in tyrosine phosphorylation of the p85 subunit, and physical association with Ras. Activation of PI 3-kinase by TNFalpha, sphingomyelinase, and C2-ceramide was inhibited by tyrosine kinase inhibitors (genistein and PP1). The stimulation of PI 3-kinase by sphingomyelinase and C2-ceramide was not observed in fibroblasts expressing dominant-negative Ras (N17) and the stimulation by TNFalpha was decreased by 70%. PI 3-kinase activation by C2-ceramide was not modified by inhibitors of acidic and neutral ceramidases, and it was not observed with the relatively inactive analog, dihydro-C2-ceramide. It is proposed that activation of Ras and PI 3-kinase by ceramide can contribute to signaling effects of TNFalpha that occur downstream of sphingomyelinase activation and result in increased fibroblasts proliferation.
- Subjects :
- Ceramide
Ceramides
Biochemistry
Receptor tyrosine kinase
Cell Line
Proto-Oncogene Proteins p21(ras)
Phosphatidylinositol 3-Kinases
chemistry.chemical_compound
Animals
Phosphatidylinositol
Molecular Biology
biology
Tumor Necrosis Factor-alpha
Kinase
Tyrosine phosphorylation
Cell Biology
Protein-Tyrosine Kinases
Rats
Cell biology
Enzyme Activation
chemistry
biology.protein
Signal transduction
Tyrosine kinase
Signal Transduction
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 274
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....3281bc6a7b826ba1e710e92d17c4efbd