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Vol. 12, Issue 11, 3618-3630, November 2001
Induces Stress Fiber Formation through
Ceramide Production: Role of Sphingosine Kinase
and¶
*Signal Transduction Research Group and
Tumor necrosis factor-Department of Biochemistry, University of Alberta,
Edmonton, Alberta, Canada T6G 2S2; Department of Cell
Biology, University of Alberta, §Division of Anatomy,
University of Alberta, Edmonton, Alberta, Canada T6G 2S2; and
Centre de Recherche en Rhumatologie et Immunologie,
Centre de Recherche du CHUQ, Laval University, Québec, Canada G1V
4G2
(TNF-) is a proinflammatory cytokine
that activates several signaling cascades. We determined the extent to
which ceramide is a second messenger for TNF--induced signaling
leading to cytoskeletal rearrangement in Rat2 fibroblasts. TNF-,
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- effects were only partially inhibited.
Dimethylsphingosine, a sphingosine kinase (SK) inhibitor, blocked
stress fiber formation by TNF- and C2-ceramide. TNF-,
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-- and C2-ceramide-induced stress fiber
formation. Our results demonstrate that stimulation by TNF-, 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--induced stress fiber formation and cytoskeletal reorganization.
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