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

FEBS Letters

Frame, Sheelagh²  Polakis, Paul³  Thomas, Gareth M.²  Cohen, Philip²  Goedert, Michel⁴  Nathke, Inke¹ 

[1] Department of Anatomy and Physiology, MSI/WTB Complex, University of Dundee, Dow Street, Dundee DD1 5EH, UK;MRC Protein Phosphorylation Unit, MSI/WTB Complex, University of Dundee, Dow Street, Dundee DD1 5EH, UK;Onyx Pharmaceuticals, 3031 Research Drive, Richmond, CA 94806, USA;MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK

关键词: Axin;    Glycogen synthase kinase-3;    β-Catenin;    FRAT1;   

DOI  :  10.1016/S0014-5793(99)01161-8

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

The Axin-dependent phosphorylation of β-catenin catalysed by glycogen synthase kinase-3 (GSK3) is inhibited during embryogenesis. This protects β-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 β-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 β-catenin phosphorylation.

【 授权许可】

Unknown