title: E-cadherin promotes EGFR-mediated cell differentiation and MUC5AC mucin expression in cultured human airway epithelial cells.
abstract: In previous work, we showed that epidermal growth factor receptor (EGFR) activation causes mucin expression in airway epithelium in vivo and in human NCI-H292 airway epithelial cells and normal human bronchial epithelial (NHBE) cells in vitro. Here we show that the cell surface adhesion molecule, E-cadherin, promotes EGFR-mediated mucin production in NCI-H292 cells in a cell density- and cell cycle-dependent fashion. The addition of the EGFR ligand, transforming growth factor (TGF)-alpha, increased MUC5AC protein expression markedly in dense, but not in sparse, cultures. MUC5AC-positive cells in dense cultures contained 2 N DNA content and did not incorporate bromodeoxyuridine, suggesting that they develop via cell differentiation and that a surface molecule involved in cell-cell contact is important for EGFR-mediated mucin production. In support of this hypothesis, in dense cultures of NCI-H292 cells and in NHBE cells at air-liquid interface, blockade of E-cadherin-mediated cell-cell contacts decreased EGFR-dependent mucin production. E-cadherin blockade also increased EGFR-dependent cell proliferation and TGF-alpha-induced EGFR tyrosine phosphorylation in dense cultures of NCI-H292 cells, suggesting that E-cadherin promotes EGFR-dependent mucin production and inhibits EGFR-dependent cell proliferation via modulation of EGFR phosphotyrosine levels. Furthermore, in dense cultures, E-cadherin blockade decreased the rate of EGFR tyrosine dephosphorylation, implicating an E-cadherin-dependent protein tyrosine phosphatase in EGFR dephosphorylation. Thus E-cadherin promotes EGFR-mediated cell differentiation and MUC5AC production, and our results suggest that this occurs via a pathway involving protein tyrosine phosphatase-dependent EGFR dephosphorylation.
authors.affiliation: Cardiovascular Research Institute, Box 0130, University of California-San Francisco, San Francisco, CA 94143-0130, USA.
authors.forename: Suil
authors.initials: S
authors.lastname: Kim
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Schein
authors.forename: Jay A
authors.initials: JA
authors.lastname: Nadel
mesh_terms: D001973:Bromodeoxyuridine / Q000494:pharmacology; D001980:Bronchi / Q000166:cytology / Q000502:physiology*; D015820:Cadherins / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D004247:DNA / Q000096:biosynthesis; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology*; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D055271:Mucin 5AC; D009077:Mucins / Q000096:biosynthesis*; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D016211:Transforming Growth Factor alpha / Q000378:metabolism / Q000494:pharmacology
chemical_list: D015820:Cadherins; C524678:MUC5AC protein, human; D055271:Mucin 5AC; D009077:Mucins; D016211:Transforming Growth Factor alpha; D004247:DNA; D066246:ErbB Receptors; D017027:Protein Tyrosine Phosphatases; D001973:Bromodeoxyuridine