Phospho-regulation of Beta-catenin adhesion and signaling functions

Abstract

Beta-catenin plays a critical structural role in cadherin-based adhesions and is also an essential co-activator of Wnt-mediated gene expression. The degree to which beta-catenin participates in these two functions is dictated by the availability of beta-catenin binding partners, and an emerging theme is that these binding interactions are regulated by phosphorylation. Inputs from various cell-signaling events can therefore impact beta-catenin function, which may be necessary for the finely tuned adhesive and signaling responses required for tissue morphogenesis.

FIGURE 1. Summary of β-catenin-mediated adhesion and signaling

See text and http://www.stanford.edu/~rnusse/wntwindow.html for details.

FIGURE 2. Phospho-regulation of β-catenin protein interactions

A: phosphorylation of cadherin residue, Y860, and β-catenin residue, Y654, by src prevents the cadherin/β catenin interaction. Also inhibitory to the cadherin/catenin interaction is phosphorylation of cadherin S846 (S840 in the human E-cadherin sequence) by CK1. In contrast, GSK3β and CK2-mediated phosphorylation of cadherin S834, S836, and S842 enhances associations with β -catenin. B: β catenin preferentially binds to phosphorylated APC/axin complex. CK1 and GSK3β hyperphosphorylate the degradation complex and increase the affinity of APC/axin for β-catenin. Once bound to APC/axin, β-catenin becomes phosphorylated at S45 by CK1 (or IKKα and cyclinD/cdk6). Subsequent phosphorylations at S33, S37, and T41 by GSK3β (or PKC) lead to ubiquitination and degradation of β-catenin. Phosphatase PP1 reverses CK1-mediated phosphorylation of axin and allows β-catenin to escape the degradation complex. Corresponding kinases and phosphorylations are highlighted in the same color. C: phosphorylation of LEF/TCF by CK2 enhances interaction with β-catenin and promotes the recruitment of β-catenin to Wnt-regulated promoters. Met-mediated phosphorylation of Y142 allows BCL9/pygopus to bind the NH₂ terminus of β-catenin, whereas phosphorylation of S552 and S675 by Akt and PKA promote interactions with additional transcriptional coactivators, such as CBP. See text for references. Arrows reflect enhanced interactions. P, phosphorylation site.