In response to transforming growth factor beta 1 ( TGF beta) stimulation, fibroblasts modify their integrin repertoire and adhesive capabilities to certain extracellular matrix proteins. Although TGF beta has been shown to increase the expression of specific alpha v integrins, the mechanisms underlying this are unknown. In this study we demonstrate that TGF beta 1 increased both beta 3 integrin subunit mRNA and protein levels as well as surface expression of alpha v beta 3 in human lung fibroblasts. TGF beta 1-induced alpha v beta 3 expression was strongly adhesion-dependent and associated with increased focal adhesion kinase and c-Src kinase phosphorylation. Inhibition of beta 3 integrin activation by the Arg-Gly-Asp tripeptide motif-specific disintegrin echistatin or alpha v beta 3 blocking antibody prevented the increase in beta 3 but not beta 5 integrin expression. In addition, echistatin inhibited TGF beta 1-induced p38 MAPK but not Smad3 activation. Furthermore, inhibition of the Src family kinases, but not focal adhesion kinase, completely abrogated TGF beta 1-induced expression of alpha v beta 3 and p38 MAPK phosphorylation but not beta 5 integrin expression and Smad3 activation. The TGF beta 1-induced alpha v beta 3 expression was blocked by pharmacologic and genetic inhibition of p38 MAPK- but not Smad2/3-, Sp1-, ERK-, phosphatidylinositol 3-kinase, and NF-kappa B-dependent pathways. Our results demonstrate that TGF beta 1 induces alpha v beta 3 integrin expression via a beta 3 integrin-, c-Src-, and p38 MAPK-dependent pathway. These data identify a novel mechanism for TGF beta 1 signaling in human lung fibroblasts by which they may contribute to normal and pathological wound healing.
Pechkovsky, D. V., Scaffidi, A., Hackett, T. L., Ballard, J., Shaheen, F., Thompson, P., ... Knight, D. A. (2008). Transforming Growth Factor β1 Induces αvβ3 Integrin Expression in Human Lung Fibroblasts via a β3 Integrin-, c-Src-, and p38 MAPK-dependent Pathway. Journal of Biological Chemistry, 283(19), 12898-12908. https://doi.org/10.1074/jbc.M708226200