title: Heregulin activation of ErbB2/ErbB3 signaling potentiates the integrity of airway epithelial barrier.
abstract: BACKGROUND
  Members of the ErbB family of the receptor protein tyrosine kinase superfamily mediate heregulin (HRG)-induced cell responses. Here we investigated HRG activation of ErbB receptors, and the role of this activation in the development of the permeability barrier in airway epithelial cells (AECs).
  
  
  METHODS
  Two airway epithelial-like cell lines, Calu-3 and 16HBE were exposed to HRG or no stimulus and were evaluated with respect to their paracellular permeability as determined by transepithelial electric resistance (TER) and fluorescein isothiocyanate (FITC)-dextran flux. Tight junctions (TJs) were assessed by immunocytochemical localization of occludin and zonula occludens-1.
  
  
  RESULTS
  HRG promoted the development of the permeability barrier and TJ formation by monolayers of Calu-3 and 16HBE cells. Calu-3 cells expressed ErbB1, ErbB2, and ErbB3, but not ErbB4, on their surface. ErbB3 knockdown by small interference RNA (siRNA) blunted the effects of HRG on the permeability barrier. ErbB3 is known as a kinase-dead receptor and relies on other members of the family for its phosphorylation. To identify its heterodimerization partner, we knocked down the expression of other ErbB family receptors. We found that HRG's effect on the permeability barrier could be significantly attenuated by transfecting cells with ErbB2 siRNA but not with EGFR siRNA.
  
  
  CONCLUSIONS
  These results indicate that HRG activation of ErbB2/ErbB3 heterodimers is essential for regulation of the permeability barrier in AECs.
authors.affiliation: Division of Respiratory Medicine, Department of Internal Medicine, Nihon University School of Medicine, 30–1 Oyaguchi-kamimachi, Itabashi-ku, Tokyo, Japan. gon@med.nihon-u.ac.jp
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Gon
authors.forename: Ken
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Masahiro
authors.initials: M
authors.lastname: Terakado
authors.forename: Akiko
authors.initials: A
authors.lastname: Sekiyama
authors.forename: Shuichiro
authors.initials: S
authors.lastname: Maruoka
authors.forename: Ikuko
authors.initials: I
authors.lastname: Takeshita
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kozu
authors.forename: Yoshimichi
authors.initials: Y
authors.lastname: Okayama
authors.forename: Chisei
authors.initials: C
authors.lastname: Ra
authors.forename: Shu
authors.initials: S
authors.lastname: Hashimoto
mesh_terms: D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D020890:Neuregulin-1 / Q000494:pharmacology*; D010539:Permeability; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000166:cytology* / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured
chemical_list: D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases