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

The Axin-dependent phosphorylation of beta-catenin catalysed by glycogen sy nthase kinase-3 (GSK3) is inhibited during embryogenesis, This protects bet a-catenin against ubiquitin-dependent proteolysis, leading to its accumulat ion 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 interac ting 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 activi ty towards other substrates, such as glycogen synthase and eIF2B, whose pho sphorylation is independent of Axin but dependent on a 'priming' phosphoryl ation, This may explain how the essential cellular functions of GSK3 can co ntinue, despite the suppression of beta-catenin phosphorylation, (C) 1999 F ederation of European Biochemical Societies.