PMID- 11694593
OWN - NLM
STAT- MEDLINE
DCOM- 20020122
LR  - 20240407
IS  - 1059-1524 (Print)
IS  - 1059-1524 (Linking)
VI  - 12
IP  - 11
DP  - 2001 Nov
TI  - Tumor necrosis factor-alpha induces stress fiber formation through ceramide 
      production: role of sphingosine kinase.
PG  - 3618-30
AB  - Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine that 
      activates several signaling cascades. We determined the extent to which ceramide 
      is a second messenger for TNF-alpha-induced signaling leading to cytoskeletal 
      rearrangement in Rat2 fibroblasts. TNF-alpha, 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-alpha effects 
      were only partially inhibited. Dimethylsphingosine, a sphingosine kinase (SK) 
      inhibitor, blocked stress fiber formation by TNF-alpha and C(2)-ceramide. 
      TNF-alpha, 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-alpha- and 
      C(2)-ceramide-induced stress fiber formation. Our results demonstrate that 
      stimulation by TNF-alpha, 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 
      approximately 70% of TNF-alpha-induced stress fiber formation and cytoskeletal 
      reorganization.
FAU - Hanna, A N
AU  - Hanna AN
AD  - Signal Transduction Research Group and Department of Biochemistry, University of 
      Alberta, Edmonton, Alberta, Canada T6G 2S2.
FAU - Berthiaume, L G
AU  - Berthiaume LG
FAU - Kikuchi, Y
AU  - Kikuchi Y
FAU - Begg, D
AU  - Begg D
FAU - Bourgoin, S
AU  - Bourgoin S
FAU - Brindley, D N
AU  - Brindley DN
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Mol Biol Cell
JT  - Molecular biology of the cell
JID - 9201390
RN  - 0 (Cytoskeletal Proteins)
RN  - 0 (N-acetylsphingosine)
RN  - 0 (PXN protein, human)
RN  - 0 (Paxillin)
RN  - 0 (Phosphoproteins)
RN  - 0 (Pxn protein, rat)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 42HK56048U (Tyrosine)
RN  - EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor))
RN  - EC 2.7.1.- (sphingosine kinase)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.2 (Focal Adhesion Kinase 1)
RN  - EC 2.7.10.2 (Focal Adhesion Protein-Tyrosine Kinases)
RN  - EC 2.7.10.2 (PTK2 protein, human)
RN  - EC 2.7.10.2 (Ptk2 protein, rat)
RN  - EC 3.1.4.12 (Sphingomyelin Phosphodiesterase)
RN  - EC 3.6.5.2 (cdc42 GTP-Binding Protein)
RN  - EC 3.6.5.2 (rac GTP-Binding Proteins)
RN  - EC 3.6.5.2 (ras Proteins)
RN  - EC 3.6.5.2 (rhoA GTP-Binding Protein)
RN  - NGZ37HRE42 (Sphingosine)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Cytoskeletal Proteins/metabolism
MH  - Cytoskeleton/metabolism/physiology
MH  - Focal Adhesion Kinase 1
MH  - Focal Adhesion Protein-Tyrosine Kinases
MH  - Humans
MH  - Paxillin
MH  - Phosphoproteins/metabolism
MH  - Phosphorylation
MH  - Phosphotransferases (Alcohol Group Acceptor)/metabolism/*physiology
MH  - Protein-Tyrosine Kinases/metabolism
MH  - Rats
MH  - Sphingomyelin Phosphodiesterase/metabolism
MH  - Sphingosine/*analogs & derivatives/*biosynthesis
MH  - Stress Fibers/metabolism/*physiology
MH  - Tumor Necrosis Factor-alpha/*metabolism/pharmacology
MH  - Tyrosine/metabolism
MH  - cdc42 GTP-Binding Protein/metabolism/physiology
MH  - rac GTP-Binding Proteins/metabolism/physiology
MH  - ras Proteins/metabolism/physiology
MH  - rhoA GTP-Binding Protein/metabolism/physiology
PMC - PMC60280
EDAT- 2001/11/06 10:00
MHDA- 2002/01/23 10:01
CRDT- 2001/11/06 10:00
PHST- 2001/11/06 10:00 [pubmed]
PHST- 2002/01/23 10:01 [medline]
PHST- 2001/11/06 10:00 [entrez]
AID - 1644 [pii]
AID - 10.1091/mbc.12.11.3618 [doi]
PST - ppublish
SO  - Mol Biol Cell. 2001 Nov;12(11):3618-30. doi: 10.1091/mbc.12.11.3618.