| First Author | Wang Y | Year | 2013 |
| Journal | J Biol Chem | Volume | 288 |
| Issue | 35 | Pages | 25646-57 |
| PubMed ID | 23888051 | Mgi Jnum | J:203539 |
| Mgi Id | MGI:5527218 | Doi | 10.1074/jbc.M113.473777 |
| Citation | Wang Y, et al. (2013) Strain-induced differentiation of fetal type II epithelial cells is mediated via the integrin alpha6beta1-ADAM17/tumor necrosis factor-alpha-converting enzyme (TACE) signaling pathway. J Biol Chem 288(35):25646-57 |
| abstractText | Mechanical forces are critical for normal fetal lung development. However, the mechanisms regulating this process are not well-characterized. We hypothesized that strain-induced release of HB-EGF and TGF-alpha is mediated via integrin-ADAM17/TACE interactions. Employing an in vitro system to simulate mechanical forces in fetal lung development, we showed that mechanical strain of fetal epithelial cells actives TACE, releases HB-EGF and TGF-alpha, and promotes differentiation. In contrast, in samples incubated with the TACE inhibitor IC-3 or in cells isolated from TACE knock-out mice, mechanical strain did not release ligands or promote cell differentiation, which were both rescued after transfection of ADAM17. Cell adhesion assay and co-immunoprecipitation experiments in wild-type and TACE knock-out cells using several TACE constructs demonstrated not only that integrins alpha6 and beta1 bind to TACE via the disintegrin domain but also that mechanical strain enhances these interactions. Furthermore, force applied to these integrin receptors by magnetic beads activated TACE and shed HB-EGF and TGF-alpha. The contribution of integrins alpha6 and beta1 to differentiation of fetal epithelial cells by strain was demonstrated by blocking their binding site with specific antibodies and by culturing the cells on membranes coated with anti-integrin alpha6 and beta1 antibodies. In conclusion, mechanical strain releases HB-EGF and TGF-alpha and promotes fetal type II cell differentiation via alpha6beta1 integrin-ADAM17/TACE signaling pathway. These investigations provide novel mechanistic information on how mechanical forces promote fetal lung development and specifically differentiation of epithelial cells. This information could be also relevant to other tissues exposed to mechanical forces. |
