title: TNF-α-converting enzyme/a disintegrin and metalloprotease-17 mediates mechanotransduction in murine tracheal epithelial cells.
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 bronchoconstriction-induced 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.
authors.affiliation: Molecular and Integrative Physiological Sciences Program, Department of Environmental Health, Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Shiomi
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Tschumperlin
authors.forename: Jin-Ah
authors.initials: JA
authors.lastname: Park
authors.forename: Susan W
authors.initials: SW
authors.lastname: Sunnarborg
authors.forename: Keisuke
authors.initials: K
authors.lastname: Horiuchi
authors.forename: Carl P
authors.initials: CP
authors.lastname: Blobel
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Drazen
mesh_terms: D051722:ADAM Proteins / Q000502:physiology*; D000072198:ADAM17 Protein; D000818:Animals; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D066257:Heparin-binding EGF-like Growth Factor; D015151:Immunoblotting; D019426:Integrases / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D008297:Male; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D013314:Stress, Mechanical; D014132:Trachea / Q000166:cytology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D014409:Tumor Necrosis Factor-alpha; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; C045073:Cre recombinase; D019426:Integrases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse