Distinct molecular forms of β-catenin are targeted to adhesive or transcriptional complexes

Abstract

β-Catenin plays essential roles in both cell–cell adhesion and Wnt signal transduction, but what precisely controls β-catenin targeting to cadherin adhesive complexes, or T-cell factor (TCF)-transcriptional complexes is less well understood. We show that during Wnt signaling, a form of β-catenin is generated that binds TCF but not the cadherin cytoplasmic domain. The Wnt-stimulated, TCF-selective form is monomeric and is regulated by the COOH terminus of β-catenin, which selectively competes cadherin binding through an intramolecular fold-back mechanism. Phosphorylation of the cadherin reverses the TCF binding selectivity, suggesting another potential layer of regulation. In contrast, the main cadherin-binding form of β-catenin is a β-catenin–α-catenin dimer, indicating that there is a distinct molecular form of β-catenin that can interact with both the cadherin and α-catenin. We propose that participation of β-catenin in adhesion or Wnt signaling is dictated by the regulation of distinct molecular forms of β-catenin with different binding properties, rather than simple competition between cadherins and TCFs for a single constitutive form. This model explains how cells can control whether β-catenin is used independently in cell adhesion and nuclear signaling, or competitively so that the two processes are coordinated and interrelated.

The Terminal Region of β-Catenin Promotes Stability by Shielding the Armadillo Repeats from the Axin-scaffold Destruction Complex

“…This interaction was also observed using purified arm domain and CTD components followed by semiquantitative Western and blot overlay analysis (39). With similar methods, two studies found that the CTD of ␤-catenin could compete its binding to the cadherin (39,47), but not TCF (47), raising the possibility that in a full-length protein the CTD may fold back along the arm domain in a closed conformation that restricts binding to some partners (27,47). However, specific binding between the CTD and the arm domain was not supported when Coomassie-stained gels were employed to quantify binding (19) or NMR spectroscopy was used to detect transient weak interactions (29).…”

PTEN-deficient intestinal stem cells initiate intestinal polyposis

“…44) does, however, suggest mechanisms by which phosphorylation at the Akt target site might participate in localization. The C-terminal portion of the protein, including R10, is implicated in the nuclear import and export of β-catenin 45 , and it is also suggested that conformational changes in this region help partition β-catenin between nuclear and membrane pools 46 . Phosphorylation of Ser552 may therefore modulate the translocation of β-catenin through nuclear pores or affect its conformation 47,48 .…”

Gli1 acts through Snail and E-cadherin to promote nuclear signaling by β-catenin

“…Participation of b-catenin in cell-cell adhesion or Wnt signaling is determined by competitive binding of b-catenin to a-catenin and the actin network versus Wnt signaling components in the cytoplasm (Gottardi and Gumbiner, 2004;Nelson and Nusse, 2004;Bienz, 2005;Gumbiner, 2005;Brembeck et al, 2006). Switching of b-catenin from cell adhesion to Wnt signaling can be induced by tyrosine phosphorylation of b-catenin, which promotes binding to BCL9-2 instead of a-catenin.…”

“…Loss of E-cad during tumor progression could likewise promote Wnt signaling (Nelson and Nusse, 2004;Bienz, 2005). However, E-cad loss-of-function in tumor cells is not often associated with increased b-catenin signaling and specific contexts in which the cadherin-bound pool of b-catenin is released for signaling remain poorly understood (van de Wetering et al, 2001;Gottardi and Gumbiner, 2004;Nelson and Nusse, 2004;Gumbiner, 2005).…”