TY - JOUR
T1 - TNF-α-converting enzyme/A disintegrin and metalloprotease - 17 mediates mechanotransduction in murine tracheal epithelial cells
AU - Shiomi, Tetsuya
AU - Tschumperlin, Daniel J.
AU - Park, Jin Ah
AU - Sunnarborg, Susan W.
AU - Horiuchi, Keisuke
AU - Blobel, Carl P.
AU - Drazen, Jeffrey M.
PY - 2011/8/1
Y1 - 2011/8/1
N2 - 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.
AB - 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.
KW - Airway remodelling
KW - Asthma
KW - TACE
UR - http://www.scopus.com/inward/record.url?scp=80051614372&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80051614372&partnerID=8YFLogxK
U2 - 10.1165/rcmb.2010-0234OC
DO - 10.1165/rcmb.2010-0234OC
M3 - Article
C2 - 21097655
AN - SCOPUS:80051614372
SN - 1044-1549
VL - 45
SP - 376
EP - 385
JO - American journal of respiratory cell and molecular biology
JF - American journal of respiratory cell and molecular biology
IS - 2
ER -