A GSK3-binding peptide from FRAT1 selectively inhibits the GSK3-catalysed phosphorylation of Axin and β-catenin

Gareth M. Thomas, Sheelagh Frame, Michel Goedert, Inke Nathke, Paul Polakis, Philip Cohen

    Research output: Contribution to journalArticle

    191 Citations (Scopus)

    Abstract

    The Axin-dependent phosphorylation of beta-catenin catalysed by glycogen synthase kinase-3 (GSK3) is inhibited during embryogenesis. This protects beta-catenin against ubiquitin-dependent proteolysis, leading to its accumulation in the nucleus, where it controls the expression of genes important for development. Frequently rearranged in advanced T-cell lymphomas 1 (FRAT1) is a mammalian homologue of a GSK3-binding protein (GBP), which appears to play a key role in the correct establishment of the dorsal-ventral axis in Xenopus laevis. Here, we demonstrate that FRATtide (a peptide corresponding to residues 188-226 of FRAT1) binds to GSK3 and prevents GSK3 from interacting with Axin. FRATtide also blocks the GSK3-catalysed phosphorylation of Axin and beta-catenin, suggesting a potential mechanism by which GBP could trigger axis formation. In contrast, FRATtide does not suppress GSK3 activity towards other substrates, such as glycogen synthase and eIF2B, whose phosphorylation is independent of Axin but dependent on a 'priming' phosphorylation. This may explain how the essential cellular functions of GSK3 can continue, despite the suppression of beta-catenin phosphorylation.
    Original languageEnglish
    Pages (from-to)247-251
    Number of pages5
    JournalFEBS Letters
    Volume458
    Issue number2
    DOIs
    Publication statusPublished - 1999

    Fingerprint

    Glycogen Synthase Kinase 3
    Catenins
    Phosphorylation
    T-cells
    T-Cell Lymphoma
    beta Catenin
    Peptides
    Carrier Proteins
    Proteolysis
    Glycogen Synthase
    Xenopus laevis
    Ubiquitin
    Embryonic Development
    Genes
    Gene Expression
    Substrates

    Cite this

    Thomas, Gareth M. ; Frame, Sheelagh ; Goedert, Michel ; Nathke, Inke ; Polakis, Paul ; Cohen, Philip. / A GSK3-binding peptide from FRAT1 selectively inhibits the GSK3-catalysed phosphorylation of Axin and β-catenin. In: FEBS Letters. 1999 ; Vol. 458, No. 2. pp. 247-251.
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    abstract = "The Axin-dependent phosphorylation of beta-catenin catalysed by glycogen synthase kinase-3 (GSK3) is inhibited during embryogenesis. This protects beta-catenin against ubiquitin-dependent proteolysis, leading to its accumulation in the nucleus, where it controls the expression of genes important for development. Frequently rearranged in advanced T-cell lymphomas 1 (FRAT1) is a mammalian homologue of a GSK3-binding protein (GBP), which appears to play a key role in the correct establishment of the dorsal-ventral axis in Xenopus laevis. Here, we demonstrate that FRATtide (a peptide corresponding to residues 188-226 of FRAT1) binds to GSK3 and prevents GSK3 from interacting with Axin. FRATtide also blocks the GSK3-catalysed phosphorylation of Axin and beta-catenin, suggesting a potential mechanism by which GBP could trigger axis formation. In contrast, FRATtide does not suppress GSK3 activity towards other substrates, such as glycogen synthase and eIF2B, whose phosphorylation is independent of Axin but dependent on a 'priming' phosphorylation. This may explain how the essential cellular functions of GSK3 can continue, despite the suppression of beta-catenin phosphorylation.",
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    A GSK3-binding peptide from FRAT1 selectively inhibits the GSK3-catalysed phosphorylation of Axin and β-catenin. / Thomas, Gareth M.; Frame, Sheelagh; Goedert, Michel; Nathke, Inke; Polakis, Paul; Cohen, Philip.

    In: FEBS Letters, Vol. 458, No. 2, 1999, p. 247-251.

    Research output: Contribution to journalArticle

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    AU - Thomas, Gareth M.

    AU - Frame, Sheelagh

    AU - Goedert, Michel

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    AU - Polakis, Paul

    AU - Cohen, Philip

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