A mode of regulation of β-catenin signaling activity in Xenopus embryos independent of its levels

The signaling activity of beta-catenin is thought to be regulated by phosphorylation of a cluster of N-terminal serines, putative sites for GSK3 beta. In the prevailing model in the literature, GSK3 beta-dependent phosphorylation of these sites targets beta-catenin for ubiquitin-mediated degradation. Wnt signaling inhibits GSK3 beta activity and this blocks degradation, allowing beta-catenin to accumulate and signal. We show here that beta-catenin activity is not regulated solely by protein stability. Mutations in the putative GSK3 beta phosphorylation sites of beta-catenin enhance its signaling activity, but this cannot be accounted for by accumulation of either total or cadherin-free protein. Instead, the mutant protein has a threefold higher specific activity than the wild type both in vivo and in an in vitro signaling assay. We conclude that the N-terminal serines convey a layer of regulation upon beta-catenin signaling in addition to the effects these sites exert upon protein stability. (C) 2000 Academic Press