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Suppression of chemically induced apoptosis but not necrosis of renal proximal tubular epithelial (LLC-PK1) cells by focal adhesion kinase (FAK). Role of FAK in maintaining focal adhesion organization after acute renal cell injury.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2001 Sep 28; Vol. 276 (39), pp. 36183-93. Date of Electronic Publication: 2001 Jul 10. - Publication Year :
- 2001
-
Abstract
- Decreased phosphorylation of focal adhesion kinase (FAK) is associated with loss of focal adhesions and actin stress fibers and precedes the onset of apoptosis in renal epithelial cells caused by nephrotoxicants (Van de Water, B., Nagelkerke, J. F., and Stevens, J. L. (1999) J. Biol. Chem. 274, 13328-13337). The role of FAK in the control of apoptosis caused by nephrotoxicants was further investigated in LLC-PK1 cells that were stably transfected with either green fluorescent protein (GFP)-FAK or dominant negative acting deletion mutants of FAK, GFP-FAT, and GFP-FRNK. GFP-FAT and GFP-FRNK delayed the formation of focal adhesions and prevented the localization of endogenous (phosphorylated) FAK at these sites. GFP-FAT and GFP-FRNK overexpression potentiated the onset of apoptosis caused by the nephrotoxicant dichlorovinyl-cysteine. This was associated with an increased activation of caspase-3. GFP-FAT also potentiated apoptosis caused by doxorubicin but not cisplatin. The potentiation of apoptosis by GFP-FAT was related to an almost complete dephosphorylation of FAK; this did not occur in cells overexpressing only GFP. This dephosphorylation was associated with a pronounced loss of focal adhesion organization in GFP-FAT cells, in association with loss of tyrosine phosphorylation of paxillin. In conclusion, the data indicate an important role of cell-matrix signaling in the control of chemically induced apoptosis; loss of FAK activity caused by toxic chemicals results in perturbations of focal adhesion organization with a subsequent inactivation of associated (signaling) molecules and loss of survival signaling.
- Subjects :
- Animals
Antineoplastic Agents pharmacology
Caspase 3
Caspases metabolism
Cell Cycle
Cell Division
Cell Survival
Cisplatin pharmacology
Cross-Linking Reagents pharmacology
Cytoskeletal Proteins metabolism
Dose-Response Relationship, Drug
Doxorubicin pharmacology
Enzyme Activation
Enzyme Inhibitors pharmacology
Focal Adhesion Protein-Tyrosine Kinases
Gene Deletion
Genes, Dominant
Green Fluorescent Proteins
LLC-PK1 Cells
Luminescent Proteins metabolism
Microscopy, Fluorescence
Paxillin
Phosphoproteins metabolism
Phosphorylation
Protein Binding
Recombinant Fusion Proteins metabolism
Signal Transduction
Swine
Time Factors
Transfection
Apoptosis
Epithelial Cells enzymology
Necrosis
Protein-Tyrosine Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 276
- Issue :
- 39
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 11447217
- Full Text :
- https://doi.org/10.1074/jbc.M102091200