Elevated ceramide concentrations in adipocytes and skeletal muscle impair PKB (protein kinase B; also known as Akt)-directed insulin signalling to key hormonal end points. An important feature of this inhibition involves the ceramide-induced activation of atypical PKCζ (protein kinase C-ζ), which associates with and negatively regulates PKB. In the present study, we demonstrate that this inhibition is critically dependent on the targeting and subsequent retention of PKCζ–PKB within CEM (caveolin-enriched microdomains), which is facilitated by kinase interactions with caveolin. Ceramide also recruits PTEN (phosphatase and tensin homologue detected on chromosome 10), a 3′-phosphoinositide phosphatase, thereby creating a repressive membrane microenvironment from which PKB cannot signal. Disrupting the structural integrity of caveolae by cholesterol depletion prevented caveolar targeting of PKCζ and PKB and suppressed kinase–caveolin association, but, importantly, also ameliorated ceramide-induced inhibition of PKB. Consistent with this, adipocytes from caveolin-1−/− mice, which lack functional caveolae, exhibit greater resistance to ceramide compared with caveolin-1+/+ adipocytes. We conclude that the recruitment and retention of PKB within CEM contribute significantly to ceramide-induced inhibition of PKB-directed signalling.
Skip Nav Destination
Follow us on Twitter @Biochem_Journal
Article navigation
March 2008
-
Cover Image
Cover Image
- PDF Icon PDF LinkFront Matter
Research Article|
February 12 2008
Targeting of PKCζ and PKB to caveolin-enriched microdomains represents a crucial step underpinning the disruption in PKB-directed signalling by ceramide
Eric Hajduch;
Eric Hajduch
1
*Centre de Recherche des Cordeliers, Paris F-75006, France
†Inserm, UMR S 872, Paris F-75006, France
‡Université Pierre et Marie Curie-Paris 6, UMR S 872, Paris F-75006, France
Search for other works by this author on:
Sophie Turban;
Sophie Turban
1
§Division of Molecular Physiology, Sir James Black Centre, College of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K.
Search for other works by this author on:
Xavier Le Liepvre;
Xavier Le Liepvre
*Centre de Recherche des Cordeliers, Paris F-75006, France
†Inserm, UMR S 872, Paris F-75006, France
‡Université Pierre et Marie Curie-Paris 6, UMR S 872, Paris F-75006, France
Search for other works by this author on:
Soazig Le Lay;
Soazig Le Lay
*Centre de Recherche des Cordeliers, Paris F-75006, France
†Inserm, UMR S 872, Paris F-75006, France
‡Université Pierre et Marie Curie-Paris 6, UMR S 872, Paris F-75006, France
Search for other works by this author on:
Christopher Lipina;
Christopher Lipina
§Division of Molecular Physiology, Sir James Black Centre, College of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K.
Search for other works by this author on:
Nikolaos Dimopoulos;
Nikolaos Dimopoulos
§Division of Molecular Physiology, Sir James Black Centre, College of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K.
Search for other works by this author on:
Isabelle Dugail;
Isabelle Dugail
*Centre de Recherche des Cordeliers, Paris F-75006, France
†Inserm, UMR S 872, Paris F-75006, France
‡Université Pierre et Marie Curie-Paris 6, UMR S 872, Paris F-75006, France
Search for other works by this author on:
Harinder S. Hundal
Harinder S. Hundal
2
§Division of Molecular Physiology, Sir James Black Centre, College of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K.
2To whom correspondence should be addressed (email [email protected]).
Search for other works by this author on:
Publisher: Portland Press Ltd
Received:
July 17 2007
Revision Received:
October 19 2007
Accepted:
November 05 2007
Accepted Manuscript online:
November 05 2007
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2008 Biochemical Society
2008
Biochem J (2008) 410 (2): 369–379.
Article history
Received:
July 17 2007
Revision Received:
October 19 2007
Accepted:
November 05 2007
Accepted Manuscript online:
November 05 2007
Citation
Eric Hajduch, Sophie Turban, Xavier Le Liepvre, Soazig Le Lay, Christopher Lipina, Nikolaos Dimopoulos, Isabelle Dugail, Harinder S. Hundal; Targeting of PKCζ and PKB to caveolin-enriched microdomains represents a crucial step underpinning the disruption in PKB-directed signalling by ceramide. Biochem J 1 March 2008; 410 (2): 369–379. doi: https://doi.org/10.1042/BJ20070936
Download citation file:
Sign in
Don't already have an account? Register
Sign in to your personal account
You could not be signed in. Please check your email address / username and password and try again.
Could not validate captcha. Please try again.
Biochemical Society Member Sign in
Sign InSign in via your Institution
Sign in via your InstitutionGet Access To This Article
Follow us on Twitter @Biochem_Journal
Open Access for all
We offer compliant routes for all authors from 2025. With library support, there will be no author nor reader charges in 5 journals. Check here |
![]() View past webinars > |