In:
Molecular Biology of the Cell, American Society for Cell Biology (ASCB), Vol. 12, No. 11 ( 2001-11), p. 3618-3630
Abstract:
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 C 2 -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 C 2 -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 C 2 -ceramide. TNF-α, sphingomyelinase, and C 2 -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 C 2 -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.
Type of Medium:
Online Resource
ISSN:
1059-1524
,
1939-4586
DOI:
10.1091/mbc.12.11.3618
Language:
English
Publisher:
American Society for Cell Biology (ASCB)
Publication Date:
2001
detail.hit.zdb_id:
1474922-1
SSG:
12
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