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Integrin 3β1–dependent β-catenin phosphorylation links epithelial Smad signaling to cell contacts

Pulmonary and Critical Care Division, Department of Medicine, and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143

Correspondence to Harold A. Chapman: hal.chapman{at}ucsf.edu

Injury-initiated epithelial to mesenchymal transition (EMT) depends on contextual signals from the extracellular matrix, suggesting a role for integrin signaling. Primary epithelial cells deficient in their prominent laminin receptor, 3β1, were found to have a markedly blunted EMT response to TGF-β1. A mechanism for this defect was explored in 3-null cells reconstituted with wild-type (wt) 3 or point mutants unable to engage laminin 5 (G163A) or epithelial cadherin (E-cadherin; H245A). After TGF-β1 stimulation, wt epithelial cells but not cells expressing the H245A mutant internalize complexes of E-cadherin and TGF-β1 receptors, generate phospho-Smad2 (p-Smad2)–pY654–β-catenin complexes, and up-regulate mesenchymal target genes. Although Smad2 phosphorylation is normal, p-Smad2–pY654–β-catenin complexes do not form in the absence of 3 or when 3β1 is mainly engaged on laminin 5 or E-cadherin in adherens junctions, leading to attenuated EMT. These findings demonstrate that 3β1 coordinates cross talk between β-catenin and Smad signaling pathways as a function of extracellular contact cues and thereby regulates responses to TGF-β1 activation.

Abbreviations used in this paper: -SMA, smooth muscle actin; AEC, alveolar epithelial cell; E-cadherin, epithelial cadherin; EMT, epithelial to mesenchymal transition; ERK, extracellular signal-regulated kinase; Fn, fibronectin; IP, immunoprecipitation; MDC, monodansylcadaverine; MMP, matrix metalloproteinase; p-Smad, phospho-Smad; shRNA, short hairpin RNA; wt, wild type.

© 2009 Kim et al.
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