TNF-α-converting enzyme/A disintegrin and metalloprotease - 17 mediates mechanotransduction in murine tracheal epithelial cells

Tetsuya Shiomi, Daniel J. Tschumperlin, Jin Ah Park, Susan W. Sunnarborg, Keisuke Horiuchi, Carl P. Blobel, Jeffrey M. Drazen

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Bronchoconstriction applies compressive stress to airway epithelial cells. We show that the application of compressive stress to cultured murine tracheal epithelial cells elicits the increased phosphorylation of extracellular signal-regulated kinase (ERK) and Akt through an epidermal growth factor receptor (EGFR)-dependent process, consistent with previous observations of the bronchoconstrictioninduced activation of EGFR in both human and murine airways. Mechanotransduction requires metalloprotease activity, indicating a pivotal role for proteolytic EGF-family ligand shedding. However, cells derived from mice with targeted deletions of the EGFR ligands Tgfα and Hb-egf showed only modest decreases in responses, even when combined with neutralizing antibodies to the EGFR ligands epiregulin and amphiregulin, suggesting redundant or compensatory roles for individual EGF family members in mechanotransduction. In contrast, cells harvested from mice with a conditional deletion of the gene encoding the TNF-α-converting enzyme (TACE/ADAM17), a sheddase for multiple EGF-family proligands, displayed a near-complete attenuation of ERK and Akt phosphorylation responses and compressive stress-induced gene regulation. Our data provide strong evidence that TACE plays a critical central role in the transduction of compressive stress.

Original languageEnglish (US)
Pages (from-to)376-385
Number of pages10
JournalAmerican journal of respiratory cell and molecular biology
Volume45
Issue number2
DOIs
StatePublished - Aug 1 2011

Keywords

  • Airway remodelling
  • Asthma
  • TACE

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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