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Molecular and Cellular Biology, May 2008, p. 3258-3272, Vol. 28, No. 10
0270-7306/08/$08.00+0     doi:10.1128/MCB.02032-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Mutation of the PDK1 PH Domain Inhibits Protein Kinase B/Akt, Leading to Small Size and Insulin Resistance{triangledown} ,{dagger}

Jose R. Bayascas,1,{ddagger} Stephan Wullschleger,1 Kei Sakamoto,1 Juan M. García-Martínez,1 Carol Clacher,2 David Komander,3,§ Daan M. F. van Aalten,3 Krishna M. Boini,4 Florian Lang,4 Christopher Lipina,5 Lisa Logie,5 Calum Sutherland,5 John A. Chudek,3 Janna A. van Diepen,6 Peter J. Voshol,6 John M. Lucocq,7 and Dario R. Alessi1*

MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland,1 College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland,2 Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland,3 Department of Physiology, University of Tübingen, Tübingen, Germany,4 Division of Pathology and Neurosciences, University of Dundee, Ninewells Hospital, Dundee, Scotland,5 Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands,6 Division of Cell Biology and Immunology, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland7

Received 12 November 2007/ Returned for modification 29 January 2008/ Accepted 26 February 2008

PDK1 activates a group of kinases, including protein kinase B (PKB)/Akt, p70 ribosomal S6 kinase (S6K), and serum and glucocorticoid-induced protein kinase (SGK), that mediate many of the effects of insulin as well as other agonists. PDK1 interacts with phosphoinositides through a pleckstrin homology (PH) domain. To study the role of this interaction, we generated knock-in mice expressing a mutant of PDK1 incapable of binding phosphoinositides. The knock-in mice are significantly small, insulin resistant, and hyperinsulinemic. Activation of PKB is markedly reduced in knock-in mice as a result of lower phosphorylation of PKB at Thr308, the residue phosphorylated by PDK1. This results in the inhibition of the downstream mTOR complex 1 and S6K1 signaling pathways. In contrast, activation of SGK1 or p90 ribosomal S6 kinase or stimulation of S6K1 induced by feeding is unaffected by the PDK1 PH domain mutation. These observations establish the importance of the PDK1-phosphoinositide interaction in enabling PKB to be efficiently activated with an animal model. Our findings reveal how reduced activation of PKB isoforms impinges on downstream signaling pathways, causing diminution of size as well as insulin resistance.

* Corresponding author. Mailing address: MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland. Phone: 44-1382 384 241. Fax: 44-1382 223 778. E-mail: d.r.alessi{at}dundee.ac.uk

{triangledown} Published ahead of print on 17 March 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Present address: Institut de Neurociències, Universitat Autònoma de Barcelona, Barcelona, Spain.

§ Present address: MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, United Kingdom.

Molecular and Cellular Biology, May 2008, p. 3258-3272, Vol. 28, No. 10
0270-7306/08/$08.00+0     doi:10.1128/MCB.02032-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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