Targeting of PKC zeta and PKB to caveolin-enriched microdomains represents a crucial step underpinning the disruption in PKB-directed signalling by ceramide

Eric Hajduch, Sophie Turban, Xavier Le Liepvre, Soazig Le Lay, Christopher Lipina, Nikolaos Dimopoulos, Isabelle Dugail, Harinder S. Hundal

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    81 Citations (Scopus)

    Abstract

    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 PKC zeta (protein kinase C-zeta), 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 PKC zeta-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 PKC zeta 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.

    Original languageEnglish
    Pages (from-to)369-379
    Number of pages11
    JournalBiochemical Journal
    Volume410
    DOIs
    Publication statusPublished - 1 Mar 2008

    Keywords

    • caveolin-enriched microdomain
    • ceramide
    • insulin receptor substrate (IRS)
    • phosphatase and tensin homologue detected on chromosome 10 (PTEN)
    • protein kinase B (PKB)-directed insulin signalling
    • protein kinase C-zeta(PK zeta)
    • PROTEIN-KINASE-C
    • PLECKSTRIN HOMOLOGY DOMAIN
    • INDUCED INSULIN-RESISTANCE
    • 3T3-L1 ADIPOCYTES
    • PLASMA-MEMBRANE
    • CELL-SURFACE
    • MUSCLE-CELLS
    • ACTIVATION
    • GLUCOSE
    • TRANSLOCATION

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