As a component of adherens junctions and the Wnt signaling pathway, beta-catenin binds cadherins, Tcf family transcription factors, and the tumor suppressor APC. We have determined the crystal structures of both unphosphorylated and phosphorylated E-cadherin cytoplasmic domain complexed with the arm repeat region of beta-catenin. The interaction spans all 12 arm repeats, and features quasi-independent binding regions that include helices which interact with both ends of the arm repeat domain and an extended stretch of 14 residues which closely resembles a portion of XTcf-3. Phosphorylation of E-cadherin results in interactions with a hydrophobic patch of beta-catenin that mimics the binding of an amphipathic XTcf-3 helix. APC contains sequences homologous to the phosphorylated region of cadherin, and is likely to bind similarly.

Beta-catenin is essential for cadherin-based cell adhesion and Wnt/Wingless growth factor signaling. In these roles, it binds to cadherins, Tcf-family transcription factors, and the tumor suppressor gene product Adenomatous Polyposis Coli (APC). A core region of beta-catenin, composed of 12 copies of a 42 amino acid sequence motif known as an armadillo repeat, mediates these interactions. The three-dimensional structure of a protease-resistant fragment of beta-catenin containing the armadillo repeat region has been determined. The 12 repeats form a superhelix of helices that features a long, positively charged groove. Although unrelated in sequence, the beta-catenin binding regions of cadherins, Tcfs, and APC are acidic and are proposed to interact with this groove.

Background: MGP inhibits tissue calcification, but underlying mechanisms are understudied. Results: In MGP null mice, TG2 ablation prevents calcifying cartilaginous vascular lesions but does not affect elastocalcinosis and elastin fragmentation associated with increased elastase adipsin. Conclusion: MGP acts via two distinct mechanisms. Significance: Our study identifies TG2 and adipsin as potential therapeutic targets in vascular disease linked to MGP deficiency.

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␤-Catenin is a structural component of adherens junctions, where it binds to the cytoplasmic domain of cadherin cell adhesion molecules. ␤-Catenin is also a transcriptional coactivator in the Wnt signaling pathway, where it binds to Tcf/Lef family transcription factors. In the absence of a Wnt signal, nonjunctional ␤-catenin is present in a multiprotein complex containing the proteins axin and adenomatous polyposis coli (APC), both of which bind directly to ␤-catenin. The thermodynamics of ␤-catenin binding to E-cadherin, Lef-1, APC, axin, and the transcriptional inhibitor ICAT have been determined by isothermal titration calorimetry. Most of the interactions showed large, unfavorable entropy changes, consistent with these ligands being natively unstructured in the absence of ␤-catenin. Phosphorylation of serine residues present in a sequence motif common to cadherins and APC increased the affinity for ␤-catenin 300 -700-fold, and surface plasmon resonance measurements revealed that phosphorylation of E-cadherin both enhanced its on rate and decreased its off rate. The effects of the N-and C-terminal "tails" that flank the ␤-catenin armadillo repeat domain on ligand binding have also been investigated using constructs lacking one or both tails. Contrary to earlier studies that employed less direct binding assays, the tails did not affect the affinity of ␤-catenin for tight ligands such as E-cadherin, Lef-1, and phosphorylated APC. However, the ␤-catenin C-terminal tail was found to decrease the affinity for the weaker ligands APC and axin, suggesting that this region may have a regulatory role in ␤-catenin degradation.The protein ␤-catenin serves several roles in the development and maintenance of multicellular organisms. It is a structural component of cell-cell contacts and is also a transcriptional coactivator in the Wnt signaling pathway that controls cell fate determination. The multiple functions of this protein depend upon its interactions with several distinct protein ligands. In adherens junctions, ␤-catenin interacts with the cytoplasmic domain of classical cadherins and with ␣-catenin, which functionally connects the cadherin-catenin complex to the actin cytoskeleton. The levels of nonjunctional ␤-catenin are determined by the presence or absence of Wnt growth factor stimulation. In the absence of a Wnt, cytosolic ␤-catenin is targeted for degradation by a multiprotein complex containing axin and the adenomatous polyposis coli protein (APC).3 The axin-APC complex binds to ␤-catenin and also recruits casein kinase 1 (CK1) and glycogen synthase kinase-3␤ (GSK-3␤). These kinases phosphorylate ␤-catenin, flagging it for destruction by the ubiquitin-proteosome pathway. In the presence of a Wnt signal, phosphorylation of ␤-catenin is inhibited. The resulting stabilized pool of ␤-catenin translocates to the nucleus, where it binds to the Tcf/Lef family transcription factors. The ␤-catenin-Tcf complex recruits general transcription factors, resulting in a complex that activates Wnt target genes. The primary s...