title: Cigarette smoke disrupts the integrity of airway adherens junctions through the aberrant interaction of p120-catenin with the cytoplasmic tail of MUC1.
abstract: 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.
authors: Francis I Proctor Foundation, University of California, San Francisco, California, USA.
authors: Lili
authors: L
authors: Zhang
authors: Marianne
authors: M
authors: Gallup
authors: Lorna
authors: L
authors: Zlock
authors: Carol
authors: C
authors: Basbaum
authors: Walter E
authors: WE
authors: Finkbeiner
authors: Nancy A
authors: NA
authors: McNamara
mesh_terms: D022005:Adherens Junctions / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001980:Bronchi / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051177:Catenins / Q000737:chemistry / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D016764:Cell Polarity / Q000187:drug effects; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018396:Mucin-1 / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D061251:Primary Cell Culture; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000009:adverse effects*; D013997:Time Factors; D014443:Tyrosine; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000095002:Delta Catenin
chemical_list: D051177:Catenins; C060192:MUC1 protein, human; D018396:Mucin-1; D047428:Protein Kinase Inhibitors; D012906:Smoke; D014443:Tyrosine; C512478:EGFR protein, human; D066246:ErbB Receptors; D019061:src-Family Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D000095002:Delta Catenin; C000722347:CTNND1 protein, human