TY - JOUR
T1 - Transforming Growth Factor β1 Induces αvβ3 Integrin Expression in Human Lung Fibroblasts via a β3 Integrin-, c-Src-, and p38 MAPK-dependent Pathway
AU - Pechkovsky, D.V.
AU - Scaffidi, Amelia
AU - Hackett, T.L.
AU - Ballard, J.
AU - Shaheen, F.
AU - Thompson, Philip
AU - Thannickal, V.J.
AU - Knight, D.A.
PY - 2008
Y1 - 2008
N2 - 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.
AB - 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.
U2 - 10.1074/jbc.M708226200
DO - 10.1074/jbc.M708226200
M3 - Article
SN - 0021-9258
VL - 283
SP - 12898
EP - 12908
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 19
ER -