FC0038
E-cadherin  -  β-catenin

Biological function
The cytosolic protein β-catenin has essential roles in cell adhesion and in signal transduction. β-catenin is a component of adherens junctions, sites of cell-cell contact in which the actin cytoskeletons of adjacent cells are linked through cadherin cell adhesion molecules β-catenin binds to the cytoplasmic domain of classical cadherins and to β-catenin, which in turn binds directly to F-actin and other actin-associated proteins. Cell junctions are dynamic and regulated assemblies, and several mechanisms, including phosphorylation of junction components, appear to control cadherin-based adhesion. Phosphorylation of E-cadherin enhances cell adhesiveness and the affinity of the E-cadherin/β-catenin complex.

Structural evidence
E_cyto residues 685–697 of E-cadherin are not visible in the unphosphorylated complex structures, suggesting that phosphorylation is required for their association with β-catenin. In the crystal structure of the phos-Ecyto/β-catenin complex, E- cadherin residues 685–694 are visible, with ordered phosphate groups present on Ser684, Ser686, and Ser692.

Biochemical evidence
The enhanced binding of phosphorylated E-cadherin or the decreased binding of E-cadherin upon phosphorylation of β-catenin Tyr654 demonstrate that the overall affinity can be modulated without completely eliminating the interaction of these two proteins. The region between E-cadherin residues 684 and 699 contains several serine residues in consensus positions for casein kinase II (CKII) - and GSK-3β -mediated phosphorylation. Substituting these serine residues with alanine reduces β-catenin/E- cadherin complex formation and diminishes cell-cell adhesion.

Structure/Mechanism
The armadillo repeat domain architecture of β-catenin complements the binding of extended polypeptides by providing a large surface-to-volume ratio and elongated interaction surface. Multiple, quasi-independent interactions provide the possibility of having a minimal ’core’ binding region while allowing other interactions to be more dynamic. Separate binding regions can be regulated independently, enabling combinatorial regulation of the interaction and the integration of multiple input signals.

Mechanism category
tethering

Posttranslational modification
Phosphorylation induces folding of the 685-694 region, and forms a stable interaction with β−catenin. Phosphorylation modulates affinity in a gradual fashion instead of an on/off switch.

Significance
Fuzziness enables multiple, quasi-independent interactions between β-catenin and E-cadherin. In this manner the different interaction sites are controlled independently, which result in combinatorial regulation via integration of multiple signals.