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

    Research output: Contribution to journalArticle

    77 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

    Cite this

    Hajduch, Eric ; Turban, Sophie ; Le Liepvre, Xavier ; Le Lay, Soazig ; Lipina, Christopher ; Dimopoulos, Nikolaos ; Dugail, Isabelle ; Hundal, Harinder S. / Targeting of PKC zeta and PKB to caveolin-enriched microdomains represents a crucial step underpinning the disruption in PKB-directed signalling by ceramide. In: Biochemical Journal. 2008 ; Vol. 410. pp. 369-379.
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    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.",
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    Targeting of PKC zeta and PKB to caveolin-enriched microdomains represents a crucial step underpinning the disruption in PKB-directed signalling by ceramide. / Hajduch, Eric; Turban, Sophie; Le Liepvre, Xavier; Le Lay, Soazig; Lipina, Christopher; Dimopoulos, Nikolaos; Dugail, Isabelle; Hundal, Harinder S.

    In: Biochemical Journal, Vol. 410, 01.03.2008, p. 369-379.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Targeting of PKC zeta and PKB to caveolin-enriched microdomains represents a crucial step underpinning the disruption in PKB-directed signalling by ceramide

    AU - Hajduch, Eric

    AU - Turban, Sophie

    AU - Le Liepvre, Xavier

    AU - Le Lay, Soazig

    AU - Lipina, Christopher

    AU - Dimopoulos, Nikolaos

    AU - Dugail, Isabelle

    AU - Hundal, Harinder S.

    PY - 2008/3/1

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    N2 - 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.

    AB - 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.

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    KW - insulin receptor substrate (IRS)

    KW - phosphatase and tensin homologue detected on chromosome 10 (PTEN)

    KW - protein kinase B (PKB)-directed insulin signalling

    KW - protein kinase C-zeta(PK zeta)

    KW - PROTEIN-KINASE-C

    KW - PLECKSTRIN HOMOLOGY DOMAIN

    KW - INDUCED INSULIN-RESISTANCE

    KW - 3T3-L1 ADIPOCYTES

    KW - PLASMA-MEMBRANE

    KW - CELL-SURFACE

    KW - MUSCLE-CELLS

    KW - ACTIVATION

    KW - GLUCOSE

    KW - TRANSLOCATION

    U2 - 10.1042/BJ20070936

    DO - 10.1042/BJ20070936

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    SP - 369

    EP - 379

    JO - Biochemical Journal

    JF - Biochemical Journal

    SN - 0264-6021

    ER -