Regulation of translation elongation factor‐2 by insulin via a rapamycin‐sensitive signalling pathway

It is well established that insulin and serum stimulate gene expression at the level of mRNA translation in animal cells, and previous studies have mainly focused on the initiation process. Here we show that, in Chinese hamster ovary cells expressing the human insulin receptor, insulin causes decrea...

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Bibliographic Details
Published in:The EMBO journal 1996-05, Vol.15 (9), p.2291-2297
Main Authors: Redpath, N. T., Foulstone, E. J., Proud, C. G.
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Androstadienes - pharmacology
Animals
Calcium-Calmodulin-Dependent Protein Kinases - antagonists & inhibitors
Calcium-Calmodulin-Dependent Protein Kinases - metabolism
CHO Cells
Cricetinae
Elongation Factor 2 Kinase
Eukaryotic Initiation Factor-2 - metabolism
Humans
Insulin - pharmacology
Kinetics
Molecular Sequence Data
Phosphorylation
Polyenes - pharmacology
Protein-Serine-Threonine Kinases - metabolism
Ribosomal Protein S6 Kinases
Signal Transduction - drug effects
Sirolimus
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Summary:It is well established that insulin and serum stimulate gene expression at the level of mRNA translation in animal cells, and previous studies have mainly focused on the initiation process. Here we show that, in Chinese hamster ovary cells expressing the human insulin receptor, insulin causes decreased phosphorylation of elongation factor eEF‐2 and that this is associated with stimulation of the rate of peptide‐chain elongation. eEF‐2 is phosphorylated by a very specific Ca 2+/calmodulin‐dependent protein kinase (eEF‐2 kinase) causing its complete inactivation. The decrease in eEF‐2 phosphorylation induced by insulin reflects a fall in eEF‐2 kinase activity. Rapamycin, a macrolide immunosuppressant which blocks the signalling pathway leading to the stimulation of the 70/85 kDa ribosomal protein S6 kinases, substantially blocks the activation of elongation, the fall in eEF‐2 phosphorylation and the decrease in eEF‐2 kinase activity, suggesting that p7O S6 kinase (p70s6k) and eEF‐2 kinase may tie on a common signalling pathway. Wortmannin, an inhibitor of phosphatidylinositide‐3‐OH kinase, had similar effects. eEF‐2 kinase was phosphorylated in vitro by purified p70s6k but this had no significant effect on the in vitro activity of eEF‐2 kinase.
ISSN:0261-4189
1460-2075
DOI:10.1002/j.1460-2075.1996.tb00582.x