title: The homeodomain transcription factors Cdx1 and Cdx2 induce E-cadherin adhesion activity by reducing beta- and p120-catenin tyrosine phosphorylation.
abstract: 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. 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, alpha-, beta-, or gamma-catenin, or p120-catenin protein levels. Additionally, no alteration in their intracellular distribution was observed. Cdx expression did not alter the coprecipitation of beta-catenin with E-cadherin; however, it did reduce p120-catenin-E-cadherin coprecipitation. Tyrosine phosphorylation of beta- and p120-catenin is known to disrupt E-cadherin-mediated cell adhesion and is associated with robust p120-catenin/E-cadherin interactions. We specifically investigated beta- and p120-catenin for tyrosine phosphorylation and found that it was significantly diminished by Cdx1 or Cdx2 expression. We restored beta- and p120-catenin tyrosine phosphorylation in Cdx2-expressing cells by knocking down the expression of protein tyrosine phosphatase 1B 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 beta- 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.
authors.affiliation: Division of Gastroenterology/650 CRB, Department of Medicine, University of Pennsylvania, 415 Curie Blvd., Philadelphia, PA 19104, USA.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Ezaki
authors.forename: Rong-Jun
authors.initials: RJ
authors.lastname: Guo
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.forename: Albert B
authors.initials: AB
authors.lastname: Reynolds
authors.forename: John P
authors.initials: JP
authors.lastname: Lynch
mesh_terms: D000818:Animals; D000071616:CDX2 Transcription Factor; D015820:Cadherins / Q000502:physiology*; D051177:Catenins; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism; D018398:Homeodomain Proteins / Q000502:physiology*; D006801:Humans; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors; D014157:Transcription Factors / Q000502:physiology*; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*; D000095002:Delta Catenin
chemical_list: D000071616:CDX2 Transcription Factor; D015820:Cadherins; D051177:Catenins; C491272:Cdx1 protein, mouse; C487514:Cdx2 protein, mouse; D015815:Cell Adhesion Molecules; D018398:Homeodomain Proteins; D010750:Phosphoproteins; D014157:Transcription Factors; D051176:beta Catenin; D014443:Tyrosine; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; C516609:Ptpn1 protein, mouse; D000095002:Delta Catenin