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J Biol Chem, Vol. 274, Issue 18, 12722-12729, April 30, 1999

A Novel Pathway for Tumor Necrosis Factor- and Ceramide Signaling Involving Sequential Activation of Tyrosine Kinase, p21^ras, and Phosphatidylinositol 3-Kinase

Atef N. Hanna^§, Edmond Y. W. Chan, James Xu^§, James C. Stone, and David N. Brindley^§

From the  Signal Transduction Laboratories, the ^§ Lipid and Lipoprotein Research Group, and the Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2S2, Canada

Treatment of confluent rat2 fibroblasts with C₂-ceramide (N-acetylsphingosine), sphingomyelinase, or tumor necrosis factor- (TNF) 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 TNF, 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 TNF 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 TNF that occur downstream of sphingomyelinase activation and result in increased fibroblasts proliferation.

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