Integrity of cell-cell contacts is a critical regulator of TGF-beta 1-induced epithelial-to-myofibroblast transition: role for beta-catenin

Am J Pathol. 2004 Dec;165(6):1955-67. doi: 10.1016/s0002-9440(10)63247-6.


Injury of the tubular epithelium and TGF-beta1-induced conversion of epithelial cells to alpha-smooth muscle actin (SMA)-expressing myofibroblasts are key features of kidney fibrosis. Since injury damages intercellular junctions and promotes fibrosis, we hypothesized that cell contacts are critical regulators of TGF-beta 1-triggered epithelial-to-mesenchymal transition (EMT). Here we show that TGF-beta 1 was unable to induce EMT in intact confluent monolayers, but three different models of injury-induced loss of epithelial integrity (subconfluence, wounding, and contact disassembly by Ca(2+)-removal) restored its EMT-inducing effect. This manifested in loss of E-cadherin, increased fibronectin production and SMA expression. TGF-beta 1 or contact disassembly alone only modestly stimulated the SMA promoter in confluent layers, but together exhibited strong synergy. Since beta-catenin is a component of intact adherens junctions, but when liberated from destabilized contacts may act as a transcriptional co-activator, we investigated its role in TGF-beta 1-provoked EMT. Contact disassembly alone induced degradation of E-cadherin and beta-catenin, but TGF-beta1 selectively rescued beta-catenin and stimulated the beta-catenin-driven reporter TopFLASH. Moreover, chelation of free beta-catenin with the N-cadherin cytoplasmic tail suppressed the TGF-beta1 plus contact disassembly-induced SMA promoter activation and protein expression. These results suggest a beta-catenin-dependent two-hit mechanism in which both an initial epithelial injury and TGF-beta 1 are required for EMT.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / genetics
  • Actins / metabolism
  • Animals
  • Cadherins / metabolism
  • Calcium / metabolism
  • Cell Adhesion*
  • Cell Communication*
  • Cytoskeletal Proteins / physiology*
  • Epithelial Cells / cytology*
  • Epithelial Cells / metabolism
  • Fibroblasts / cytology*
  • Fibroblasts / metabolism
  • Fibronectins / metabolism
  • Kidney / metabolism
  • LLC-PK1 Cells
  • Muscle, Smooth / metabolism
  • Myocytes, Smooth Muscle / cytology*
  • Myocytes, Smooth Muscle / metabolism
  • Promoter Regions, Genetic / genetics
  • Swine
  • Trans-Activators / physiology*
  • Transforming Growth Factor beta / pharmacology*
  • Transforming Growth Factor beta1
  • beta Catenin


  • Actins
  • Cadherins
  • Cytoskeletal Proteins
  • Fibronectins
  • Trans-Activators
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • beta Catenin
  • Calcium