Transforming growth factor beta1 induces alphavbeta3 integrin expression in human lung fibroblasts via a beta3 integrin-, c-Src-, and p38 MAPK-dependent pathway.
In response to transforming growth factor beta1 (TGFbeta) stimulation, fibroblasts modify their integrin repertoire and adhesive capabilities to certain extracellular matrix proteins. Although TGFbeta has been shown to increase the expression of specific alphav integrins, the mechanisms underlying this are unknown. In this study we demonstrate that TGFbeta1 increased both beta3 integrin subunit mRNA and protein levels as well as surface expression of alphavbeta3 in human lung fibroblasts. TGFbeta1-induced alphavbeta3 expression was strongly adhesion-dependent and associated with increased focal adhesion kinase and c-Src kinase phosphorylation. Inhibition of beta3 integrin activation by the Arg-Gly-Asp tripeptide motif-specific disintegrin echistatin or alphavbeta3 blocking antibody prevented the increase in beta3 but not beta5 integrin expression. In addition, echistatin inhibited TGFbeta1-induced p38 MAPK but not Smad3 activation. Furthermore, inhibition of the Src family kinases, but not focal adhesion kinase, completely abrogated TGFbeta1-induced expression of alphavbeta3 and p38 MAPK phosphorylation but not beta5 integrin expression and Smad3 activation. The TGFbeta1-induced alphavbeta3 expression was blocked by pharmacologic and genetic inhibition of p38 MAPK- but not Smad2/3-, Sp1-, ERK-, phosphatidylinositol 3-kinase, and NF-kappaB-dependent pathways. Our results demonstrate that TGFbeta1 induces alphavbeta3 integrin expression via a beta3 integrin-, c-Src-, and p38 MAPK-dependent pathway. These data identify a novel mechanism for TGFbeta1 signaling in human lung fibroblasts by which they may contribute to normal and pathological wound healing.
Pechkovsky
Dmitri V
DV
University of British Columbia, Vancouver, British Columbia V6Z1Y6, Canada.
Scaffidi
Amelia K
AK
Hackett
Tillie L
TL
Ballard
Joanne
J
Shaheen
Furquan
F
Thompson
Philip J
PJ
Thannickal
Victor J
VJ
Knight
Darryl A
DA
D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D039661:Integrin beta3 / Q000378:metabolism*; D008168:Lung / Q000166:cytology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D051785:Smad Proteins / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D039302:Integrin alphaVbeta3; D039661:Integrin beta3; D047428:Protein Kinase Inhibitors; D051785:Smad Proteins; D016329:Sp1 Transcription Factor; D053773:Transforming Growth Factor beta1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D016392:Proto-Oncogene Proteins pp60(c-src); D048051:p38 Mitogen-Activated Protein Kinases