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Molecular and Cellular Biology, November 2003, p. 7794-7808, Vol. 23, No. 21
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.21.7794-7808.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Ceramide Disables 3-Phosphoinositide Binding to the Pleckstrin Homology Domain of Protein Kinase B (PKB)/Akt by a PKC{zeta}-Dependent Mechanism

Darren J. Powell,1 Eric Hajduch,1 Gursant Kular,2 and Harinder S. Hundal1*

Division of Molecular Physiology,1 MRC Protein Phosphorylation Unit, MSI/WTB Complex, Faculty of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom2

Received 7 March 2003/ Returned for modification 15 May 2003/ Accepted 25 July 2003

Ceramide is generated in response to numerous stress-inducing stimuli and has been implicated in the regulation of diverse cellular responses, including cell death, differentiation, and insulin sensitivity. Recent evidence indicates that ceramide may regulate these responses by inhibiting the stimulus-mediated activation of protein kinase B (PKB), a key determinant of cell fate and insulin action. Here we show that inhibition of this kinase involves atypical PKC{zeta}, which physically interacts with PKB in unstimulated cells. Insulin reduces the PKB-PKC{zeta} interaction and stimulates PKB. However, dissociation of the kinase complex and the attendant hormonal activation of PKB were prevented by ceramide. Under these circumstances, ceramide activated PKC{zeta}, leading to phosphorylation of the PKB-PH domain on Thr34. This phosphorylation inhibited phosphatidylinositol 3,4,5-trisphosphate (PIP3) binding to PKB, thereby preventing activation of the kinase by insulin. In contrast, a PKB-PH domain with a T34A mutation retained the ability to bind PIP3 even in the presence of a ceramide-activated PKC{zeta} and, as such, expression of PKB T34A mutant in L6 cells was resistant to inhibition by ceramide treatment. Inhibitors of PKC{zeta} and a kinase-dead PKC{zeta} both antagonized the inhibitory effect of ceramide on PKB. Since PKB confers a prosurvival signal and regulates numerous pathways in response to insulin, suppressing its activation by a PKC{zeta}-dependent process may be one mechanism by which ceramide promotes cell death and induces insulin resistance.

* Corresponding author. Mailing address: Division of Molecular Physiology, School of Life Sciences, MSI/WTB Complex, University of Dundee, Dundee, United Kingdom. Phone: (44) 1382-344969. Fax: (44) 1382-345507. E-mail: h.s.hundal{at}dundee.ac.uk.

Molecular and Cellular Biology, November 2003, p. 7794-7808, Vol. 23, No. 21
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.21.7794-7808.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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