Considerable biochemical and pharmacological evidence suggests that the activation of ribosomal protein S6 kinases (S6Ks) by activated receptor tyrosine kinases involves multiple co-ordinated input signals. However, the identities of many of these inputs remain poorly described, and their precise involvement in S6K activation has been the subject of great investigative effort. In the present study, we have shown that 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP1), a selective inhibitor of the Src family of non-receptor tyrosine kinases, interferes with the activation of 70 and 85kDa S6K gene products (p70S6K1 and p85S6K1) by insulin, insulin-like growth factor 1, sodium orthovanadate and activated alleles of phosphoinositide 3-kinase and H-Ras. PP1 also impedes the activation of AKT/protein kinase B and the extracellular signal-regulated protein kinases 1 and 2 by these various stimuli. Insulin-like growth factor 1 was observed to induce a sustained increase in c-Src autophosphorylation as revealed using anti-phospho-Y416 antisera, but this effect was absent from the cells treated with PP1. To conclude, an activated allele of p70S6K1 is compared with the wild-type allele, resistant to inhibition by PP1 when co-expressed with phosphoinositide-dependent kinase 1 (PDK1), suggesting that PP1 affects p70S6K1 via a PDK1-independent pathway. Thus activation of Src may supply a necessary signal for the activation of p70S6K1 and possibly other S6Ks.
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August 2002
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Research Article|
August 15 2002
The Src-family tyrosine kinase inhibitor PP1 interferes with the activation of ribosomal protein S6 kinases
O. Jameel SHAH;
O. Jameel SHAH
Department of Cellular and Molecular Physiology, College of Medicine, The Pennsylvania State University, 500 University Drive, Hershey, PA 17033, U.S.A.
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Scot R. KIMBALL;
Scot R. KIMBALL
Department of Cellular and Molecular Physiology, College of Medicine, The Pennsylvania State University, 500 University Drive, Hershey, PA 17033, U.S.A.
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Leonard S. JEFFERSON
Leonard S. JEFFERSON
1
Department of Cellular and Molecular Physiology, College of Medicine, The Pennsylvania State University, 500 University Drive, Hershey, PA 17033, U.S.A.
1To whom correspondence should be addressed (e-mail jjefferson@psu.edu).
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Publisher: Portland Press Ltd
Received:
January 30 2002
Revision Received:
April 26 2002
Accepted:
May 15 2002
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2002
2002
Biochem J (2002) 366 (1): 57–62.
Article history
Received:
January 30 2002
Revision Received:
April 26 2002
Accepted:
May 15 2002
Citation
O. Jameel SHAH, Scot R. KIMBALL, Leonard S. JEFFERSON; The Src-family tyrosine kinase inhibitor PP1 interferes with the activation of ribosomal protein S6 kinases. Biochem J 15 August 2002; 366 (1): 57–62. doi: https://doi.org/10.1042/bj20020198
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