The homeodomain transcription factors Cdx1 and Cdx2 are regulators of intestine-specific gene expression. They also regulate intestinal cell differentiation and proliferation, however these effects are poorly understood. Previously, we have shown that expression of Cdx1 or Cdx2 in human Colo 205 cells induces a mature colonocyte morphology characterized by the induction of a polarized, columnar shape with apical microvilli, and strong cell-cell adhesion. In order to elucidate the mechanism underlying this phenomenon, we investigated the adherens junction complex. Cdx1 or Cdx2 expression reduced Colo 205 cell migration and invasion in vitro, suggesting a physiologically significant change in cadherin function. However, Cdx expression did not significantly effect E-cadherin, -, -, -, or p120-catenin protein levels. Additionally, no alteration in their intracellular distribution was observed. Cdx expression did not alter the co-precipitation of -catenin with E-cadherin, however it did reduce p120-catenin-E-cadherin co-precipitation. Tyrosine phosphorylation of - and p120-catenin is known to disrupt E-cadherin mediated cell adhesion and is associated with robust p120-catenin/E-cadherin interactions. We investigated - and p120-catenin for tyrosine phosphorylation, and found it was significantly diminished by Cdx1 or Cdx2 expression. We restored - and p120-catenin tyrosine phosphorylation in Cdx2-expressing cells by knocking-down the expression of the protein tyrosine phosphatase PTP1B, and noted a significant decline in cell-cell adhesion. We conclude that Cdx expression in Colo 205 cells induces E-cadherin-dependent cell-cell adhesion by reducing - and p120-catenin tyrosine phosphorylation. Ascertaining the mechanism for this novel Cdx effect may improve our understanding of the regulation of cell-cell adhesion in the colonic epithelium.