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The extracellular signal-regulated kinase pathway regulates the phosphorylation of 4E-BP1 at multiple sites

Record type: Article

The phorbol ester, 12-O-tetradecanoylphorbol 13-acetate (TPA), a potent stimulator of Erk, leads to the phosphorylation of 4E-BP1 and its dissociation from eIF4E. In contrast to agonists such as insulin, this occurs independently of PKB activation. In this report, we investigate the mechanism by which TPA regulates 4E-BP1 phosphorylation. Treatment of HEK293 cells with TPA was found to result in the phosphorylation of 4E-BP1 at Ser64, Thr69, and Thr36/45. The TPA-stimulated phosphorylation of all these sites is sensitive to inhibitors of MEK and to the inhibitor of mTOR, rapamycin, indicating that inputs from both mTOR and MEK are required for the regulation of 4E-BP1 phosphorylation by TPA. Indeed, evidence is presented that mTOR may initially be required for the phosphorylation of Thr45 in a priming step, which is necessary for the subsequent phosphorylation of Ser64 and Thr69 through an Erk-dependent pathway. Overexpression of constitutively active MEK in HEK293 cells resulted both in the phosphorylation of 4E-BP1 at Ser64 and Thr36/45 and its release from eIF4E. In this case, the phosphorylation of these sites was also blocked by inhibitors of MEK or by rapamycin. In conclusion, the Erk pathway, via mechanisms also requiring mTOR, regulates the phosphorylation of multiple sites in 4E-BP1 in vivo and this is sufficient for the release of 4E-BP1 from eIF4E.

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Citation

Herbert, T.P., Tee, A.R. and Proud, C.G. (2002) The extracellular signal-regulated kinase pathway regulates the phosphorylation of 4E-BP1 at multiple sites The Journal of Biological Chemistry, 277, (13), pp. 11591-11596. (doi:10.1074/jbc.M110367200).

More information

Published date: 1 March 2002

Identifiers

Local EPrints ID: 56644
URI: http://eprints.soton.ac.uk/id/eprint/56644
ISSN: 0021-9258
PURE UUID: 85bc932c-92c5-44b4-a34a-e9046bd48093

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Date deposited: 07 Aug 2008
Last modified: 17 Jul 2017 14:30

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Contributors

Author: T.P. Herbert
Author: A.R. Tee
Author: C.G. Proud

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