Cigarette smoke induces epidermal growth factor receptor-dependent redistribution of apical MUC1 and junctional beta-catenin in polarized human airway epithelial cells.
Cigarette smoke (CS) accounts for nearly 90% of lung cancer deaths worldwide; however, an incomplete understanding of how CS initiates preneoplastic changes in the normal airway hinders early diagnosis. Short-term exposure to CS causes aberrant activation of epidermal growth factor receptor (EGFR) and canonical Wnt/beta-catenin signaling pathways in human bronchial epithelial (HBE) cells. We hypothesize that this response is elicited through the disruption of spatially segregated cell membrane proteins in the polarized airway epithelium. Using an in vitro model of highly differentiated HBE cells, we observed membrane characteristics consistent with the native airway, including the presence of a membrane mucin, MUC1, at the apical cell pole, beta-catenin at the apical-lateral membrane, and EGFR at the basolateral membrane. Following exposure to smoke, intercellular spaces enlarge and cilia disappear. This histopathology is accompanied by molecular events that include perinuclear trafficking of basolateral EGFR, EGFR phosphorylation, pEGFR-mediated phosphorylation of MUC1's cytoplasmic tail (CT), loss of E-cadherin/beta-catenin complexes at the adherens junctions (AJs), intracellular formation and nuclear shuffling of beta-catenin/MUC1-CT complexes, and, ultimately, up-regulation and nuclear localization of Wnt nuclear effector, Lef-1. In the presence of EGFR inhibitor, AG1478, CS-induced histopathology and molecular events were inhibited. These data point to EGFR as a portal through which CS mediates its damaging effects on AJ-mediated cell polarity and activation of canonical Wnt/beta-catenin signaling.
Chen
Ying-Ting
YT
University of California, San Francisco, Francis I. Proctor Foundation, San Francisco, CA 94143, USA. nancy.mcnamara@ucsf.edu
Gallup
Marianne
M
Nikulina
Karina
K
Lazarev
Stanislav
S
Zlock
Lorna
L
Finkbeiner
Walter
W
McNamara
Nancy
N
D022005:Adherens Junctions / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002458:Cell Fractionation; D016764:Cell Polarity; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008168:Lung / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018613:Microscopy, Confocal; D018396:Mucin-1 / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D015398:Signal Transduction; D012906:Smoke; D014026:Nicotiana; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
C060192:MUC1 protein, human; D018396:Mucin-1; D012906:Smoke; D051176:beta Catenin; D066246:ErbB Receptors