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Volume 431, Issue 2
October 2010
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Research Article| September 28 2010
LauraR. Pearce;
LauraR. Pearce 1
*MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, U.K.
1Correspondence may be addressed to either of these authors (email l.r.pearce@dundee.ac.uk or d.r.alessi@dundee.ac.uk).
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GordonR. Alton;
GordonR. Alton
†Pfizer Global Research and Development, San Diego, CA 92121, U.S.A.
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DanielT. Richter;
DanielT. Richter
†Pfizer Global Research and Development, San Diego, CA 92121, U.S.A.
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JohnC. Kath;
JohnC. Kath
†Pfizer Global Research and Development, San Diego, CA 92121, U.S.A.
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Laura Lingardo;
Laura Lingardo
†Pfizer Global Research and Development, San Diego, CA 92121, U.S.A.
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Justin Chapman;
Justin Chapman
†Pfizer Global Research and Development, San Diego, CA 92121, U.S.A.
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Catherine Hwang;
Catherine Hwang
†Pfizer Global Research and Development, San Diego, CA 92121, U.S.A.
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DarioR. Alessi
DarioR. Alessi 1
*MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, U.K.
1Correspondence may be addressed to either of these authors (email l.r.pearce@dundee.ac.uk or d.r.alessi@dundee.ac.uk).
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Author and article information
Publisher: Portland Press Ltd
Received: July 09 2010
Revision Received: August 11 2010
Accepted: August 12 2010
Accepted Manuscript online: August 12 2010
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2010 Biochemical Society
2010
Biochem J (2010) 431 (2): 245–255.
Article history
Received:
July 09 2010
Revision Received:
August 11 2010
Accepted:
August 12 2010
Accepted Manuscript online:
August 12 2010
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A commentary has been published: A new tool to dissect the function of p70 S6 kinase
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Citation
LauraR. Pearce, GordonR. Alton, DanielT. Richter, JohnC. Kath, Laura Lingardo, Justin Chapman, Catherine Hwang, DarioR. Alessi; Characterization of PF-4708671, a novel and highly specific inhibitor of p70 ribosomal S6 kinase (S6K1). Biochem J 15 October 2010; 431 (2): 245–255. doi: https://doi.org/10.1042/BJ20101024
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S6K1 (p70 ribosomal S6 kinase 1) is activated by insulin and growth factors via the PI3K (phosphoinositide 3-kinase) and mTOR (mammalian target of rapamycin) signalling pathways. S6K1 regulates numerous processes, such as protein synthesis, growth, proliferation and longevity, and its inhibition has been proposed as a strategy for the treatment of cancer and insulin resistance. In the present paper we describe a novel cell-permeable inhibitor of S6K1, PF-4708671, which specifically inhibits the S6K1 isoform with a Ki of 20 nM and IC50 of 160 nM. PF-4708671 prevents the S6K1-mediated phosphorylation of S6 protein in response to IGF-1 (insulin-like growth factor 1), while having no effect upon the PMA-induced phosphorylation of substrates of the highly related RSK (p90 ribosomal S6 kinase) and MSK (mitogen- and stress-activated kinase) kinases. PF-4708671 was also found to induce phosphorylation of the T-loop and hydrophobic motif of S6K1, an effect that is dependent upon mTORC1 (mTOR complex 1). PF-4708671 is the first S6K1-specific inhibitor to be reported and will be a useful tool for delineating S6K1-specific roles downstream of mTOR.
Keywords:
Akt/protein kinase B (PKB), cancer, kinase inhibitor, phosphoinositide 3-kinase (PI3K), p70 ribosomal S6 kinase (S6K), serum- and glucocorticoid-induced protein kinase (SGK)
© The Authors Journal compilation © 2010 Biochemical Society
2010
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