Osmotic Stress Inhibits p70/85 S6 Kinase through Activation of a Protein Phosphatase

While studying the stress regulation of p70/85 S6 kinase (S6K), we observed that anisomycin and UV light stimulated S6K activity, but that sorbitol inactivated S6K. Pretreatment with hyperosmotic stress also prevented the activation of S6K by both 12-O-tetradecanoylphorbol-13-acetate and anisomycin....

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Bibliographic Details
Published in:The Journal of biological chemistry 1999-08, Vol.274 (35), p.24731-24736
Main Authors: Parrott, Louis A., Templeton, Dennis J.
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing
Animals
Carrier Proteins
Cell Cycle Proteins
Cell Line
Chlorocebus aethiops
Enzyme Activation
Humans
Marine Toxins
Mutation
Osmotic Pressure
Oxazoles - pharmacology
Phosphoprotein Phosphatases - metabolism
Phosphoproteins - metabolism
Phosphorylation
Protein-Serine-Threonine Kinases - metabolism
Ribosomal Protein S6 Kinases - antagonists & inhibitors
Sirolimus - pharmacology
Ultraviolet Rays
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Summary:While studying the stress regulation of p70/85 S6 kinase (S6K), we observed that anisomycin and UV light stimulated S6K activity, but that sorbitol inactivated S6K. Pretreatment with hyperosmotic stress also prevented the activation of S6K by both 12-O-tetradecanoylphorbol-13-acetate and anisomycin. Comparison of sorbitol and rapamycin revealed that both agents inactivated S6K and caused dephosphorylation of Ser/Thr-Pro sites in the COOH terminus of S6K, including Thr412, a residue essential to S6K regulation, as determined by phospho-specific antibodies. Rapamycin-resistant S6K truncation mutants were similarly resistant to deactivation by sorbitol. Additionally, the PHAS-1 mobility shift, which is sensitive to rapamycin, was also found to be sensitive to osmotic stress. Experiments using the p38 inhibitor SB203580 and dominant negative mutants involving both stress-activated protein kinase/c-Jun NH2-terminal kinase and p38 stress pathways indicated that these pathways are probably not involved in osmotic stress inhibition of S6K. Examining the potential involvement of a phosphatase, we found that sodium pyrophosphate, sodium vanadate, cyclosporin A, tautomycin, and okadaic acid had no effect on osmotic stress inhibition of S6K. However, calyculin A prevented both rapamycin- and sorbitol-mediated deactivation of S6K. Our results suggest that osmotic stress and rapamycin act through a calyculin A-sensitive phosphatase to cause dephosphorylation and deactivation of S6K.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.274.35.24731