Transforming Growth Factor β1 Induces αvβ3 Integrin Expression in Human Lung Fibroblasts via a β3 Integrin-, c-Src-, and p38 MAPK-dependent Pathway

D.V. Pechkovsky, Amelia Scaffidi, T.L. Hackett, J. Ballard, F. Shaheen, Philip Thompson, V.J. Thannickal, D.A. Knight

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Abstract

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.
Original languageEnglish
Pages (from-to)12898-12908
JournalJournal of Biological Chemistry
Volume283
Issue number19
DOIs
Publication statusPublished - 2008

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