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Cigarette smoke disrupts the integrity of airway adherens junctions through the aberrant interaction of p120‐catenin with the cytoplasmic tail of MUC1
Author(s) -
Zhang Lili,
Gallup Marianne,
Zlock Lorna,
Basbaum Carol,
Finkbeiner Walter E.,
McNamara Nancy A.
Publication year - 2013
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4070
Subject(s) - adherens junction , microbiology and biotechnology , catenin , muc1 , cadherin , cytoplasm , beta catenin , chemistry , cancer research , biology , cell , mucin , wnt signaling pathway , signal transduction , biochemistry
Adherens junctions (AJs) containing epithelial cadherin (E‐cad) bound to p120‐catenin (p120ctn) and β‐catenin (β‐ctn) play a crucial role in regulating cell–cell adhesion. Cigarette smoke abrogates cell–cell adhesion between epithelial cells by disrupting E‐cad, a hallmark of epithelial–mesenchymal transition (EMT), yet the underlying mechanism remains unknown. We used an organotypic culture of primary human bronchial epithelial (HBE) cells treated with smoke‐concentrated medium (Smk) to establish an essential role for the interaction between p120ctn and the cytoplasmic tail of MUC1 (MUC1‐CT) in regulating E‐cad disruption. Within the first 4 h of smoke exposure, apical MUC1‐CT repositioned to the basolateral membrane of pseudo‐stratified HBE cells, where it interacted with p120ctn. A time‐dependent increase in MUC1‐CT/p120ctn complexes occurred in conjunction with a time‐dependent dissociation of p120ctn/E‐cad/β‐ctn complexes, as well as the coordinated degradation of p120ctn and E‐cad. Interestingly, Smk induced a similar interaction between MUC1‐CT and β‐ctn, but this occurred 44 h after MUC1‐CT's initial interaction with p120ctn, and well after the AJs were destroyed. Blocking MUC1‐CT's interaction with p120ctn using a MUC1‐CT dominant‐negative peptide, PMIP, successfully abolished Smk's disruptive effects on AJs and recovered apical‐basolateral polarity of HBE cells. The MUC1‐CT/p120ctn interaction was highly dependent on EGFR/Src/Jnk‐mediated tyrosine phosphorylation (TyrP) of MUC1‐CT. Accordingly, EGFR, Src or Jnk inhibitors (AG1478, PP2, SP600125, respectively) abrogated Smk‐induced MUC1‐CT‐TyrP, MUC1‐CT/p120ctn interaction, AJ disruption, and loss of cellular polarity. Our work identified MUC1‐CT and p120ctn as important regulators of epithelial polarity and cell‐cell adhesion during a smoke‐induced EMT‐like process. Novel therapeutics designed to inhibit MUC1‐CT/p120ctn complex formation may prevent EMT in the smoker's airway. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.