Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B

Darren A. E. Cross, Dario R. Alessi, Philip Cohen, Mirjana Andjelkovich, Brian A. Hemmings

    Research output: Contribution to journalLetter

    3874 Citations (Scopus)

    Abstract

    GLYCOGEN synthase kinase-3 (GSK3)1 is implicated in the regulation of several physiological processes, including the control of glycogen2 and protein3 synthesis by insulin, modulation of the transcription factors AP-1 and CREB4–6, the specification of cell fate in Drosophila 7 and dorsoventral patterning in Xenopus embryos8. GSK3 is inhibited by serine phosphorylation in response to insulin or growth factors3,9–11 and in vitro by either MAP kinase-activated protein (MAPKAP) kinase-1 (also known as p90rsk) or p70 ribosomal S6 kinase (p70S6k)12,13. Here we show, however, that agents which prevent the activation of both MAPKAP kinase-1 and p70S6k by insulin in vivo do not block the phosphorylation and inhibition of GSK3. Another insulin-stimulated protein kinase inactivates GSK3 under these conditions, and we demonstrate that it is the product of the proto-oncogene protein kinase B (PKB, also known as Akt/RAC). Like the inhibition of GSK3 (refs 10, 14), the activation of PKB is prevented by inhibitors of phosphatidylinositol (PI) 3-kinase.
    Original languageEnglish
    Pages (from-to)785-789
    Number of pages5
    JournalNature
    Volume378
    DOIs
    Publication statusPublished - 28 Dec 1995

    Fingerprint

    Glycogen Synthase Kinase 3
    Proto-Oncogene Proteins c-akt
    Phosphotransferases
    Insulin
    90-kDa Ribosomal Protein S6 Kinases
    70-kDa Ribosomal Protein S6 Kinases
    Proto-Oncogene Proteins
    Phosphorylation
    Phosphatidylinositol 3-Kinase
    Physiological Phenomena
    Transcription Factor AP-1
    Xenopus
    Protein Kinases
    Serine
    Drosophila
    Growth

    Cite this

    Cross, Darren A. E. ; Alessi, Dario R. ; Cohen, Philip ; Andjelkovich, Mirjana ; Hemmings, Brian A. / Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. In: Nature. 1995 ; Vol. 378. pp. 785-789.
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    title = "Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B",
    abstract = "GLYCOGEN synthase kinase-3 (GSK3)1 is implicated in the regulation of several physiological processes, including the control of glycogen2 and protein3 synthesis by insulin, modulation of the transcription factors AP-1 and CREB4–6, the specification of cell fate in Drosophila 7 and dorsoventral patterning in Xenopus embryos8. GSK3 is inhibited by serine phosphorylation in response to insulin or growth factors3,9–11 and in vitro by either MAP kinase-activated protein (MAPKAP) kinase-1 (also known as p90rsk) or p70 ribosomal S6 kinase (p70S6k)12,13. Here we show, however, that agents which prevent the activation of both MAPKAP kinase-1 and p70S6k by insulin in vivo do not block the phosphorylation and inhibition of GSK3. Another insulin-stimulated protein kinase inactivates GSK3 under these conditions, and we demonstrate that it is the product of the proto-oncogene protein kinase B (PKB, also known as Akt/RAC). Like the inhibition of GSK3 (refs 10, 14), the activation of PKB is prevented by inhibitors of phosphatidylinositol (PI) 3-kinase.",
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    year = "1995",
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    Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. / Cross, Darren A. E.; Alessi, Dario R.; Cohen, Philip; Andjelkovich, Mirjana; Hemmings, Brian A.

    In: Nature, Vol. 378, 28.12.1995, p. 785-789.

    Research output: Contribution to journalLetter

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    T1 - Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B

    AU - Cross, Darren A. E.

    AU - Alessi, Dario R.

    AU - Cohen, Philip

    AU - Andjelkovich, Mirjana

    AU - Hemmings, Brian A.

    PY - 1995/12/28

    Y1 - 1995/12/28

    N2 - GLYCOGEN synthase kinase-3 (GSK3)1 is implicated in the regulation of several physiological processes, including the control of glycogen2 and protein3 synthesis by insulin, modulation of the transcription factors AP-1 and CREB4–6, the specification of cell fate in Drosophila 7 and dorsoventral patterning in Xenopus embryos8. GSK3 is inhibited by serine phosphorylation in response to insulin or growth factors3,9–11 and in vitro by either MAP kinase-activated protein (MAPKAP) kinase-1 (also known as p90rsk) or p70 ribosomal S6 kinase (p70S6k)12,13. Here we show, however, that agents which prevent the activation of both MAPKAP kinase-1 and p70S6k by insulin in vivo do not block the phosphorylation and inhibition of GSK3. Another insulin-stimulated protein kinase inactivates GSK3 under these conditions, and we demonstrate that it is the product of the proto-oncogene protein kinase B (PKB, also known as Akt/RAC). Like the inhibition of GSK3 (refs 10, 14), the activation of PKB is prevented by inhibitors of phosphatidylinositol (PI) 3-kinase.

    AB - GLYCOGEN synthase kinase-3 (GSK3)1 is implicated in the regulation of several physiological processes, including the control of glycogen2 and protein3 synthesis by insulin, modulation of the transcription factors AP-1 and CREB4–6, the specification of cell fate in Drosophila 7 and dorsoventral patterning in Xenopus embryos8. GSK3 is inhibited by serine phosphorylation in response to insulin or growth factors3,9–11 and in vitro by either MAP kinase-activated protein (MAPKAP) kinase-1 (also known as p90rsk) or p70 ribosomal S6 kinase (p70S6k)12,13. Here we show, however, that agents which prevent the activation of both MAPKAP kinase-1 and p70S6k by insulin in vivo do not block the phosphorylation and inhibition of GSK3. Another insulin-stimulated protein kinase inactivates GSK3 under these conditions, and we demonstrate that it is the product of the proto-oncogene protein kinase B (PKB, also known as Akt/RAC). Like the inhibition of GSK3 (refs 10, 14), the activation of PKB is prevented by inhibitors of phosphatidylinositol (PI) 3-kinase.

    U2 - 10.1038/378785a0

    DO - 10.1038/378785a0

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