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J. Biol. Chem., Vol. 283, Issue 19, 12898-12908, May 9, 2008

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Transforming Growth Factor β1 Induces vβ3 Integrin Expression in Human Lung Fibroblasts via a β3 Integrin-, c-Src-, and p38 MAPK-dependent Pathway^*

Dmitri V. Pechkovsky, Amelia K. Scaffidi, Tillie L. Hackett^¶, Joanne Ballard, Furquan Shaheen, Philip J. Thompson, Victor J. Thannickal^||, and Darryl A. Knight^¶1

From the James Hogg iCAPTURE Centre for Cardiovascular and Respiratory Research, ^¶Department of Anaesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, British Columbia V6Z1Y6, Canada, Lung Institute of Western Australia and Centre for Asthma, Allergy and Respiratory Research, University of Western Australia, Nedlands 6009, Western Australia, and ^||Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109

In response to transforming growth factor β1 (TGFβ) stimulation, fibroblasts modify their integrin repertoire and adhesive capabilities to certain extracellular matrix proteins. Although TGFβ has been shown to increase the expression of specific v integrins, the mechanisms underlying this are unknown. In this study we demonstrate that TGFβ1 increased both β3 integrin subunit mRNA and protein levels as well as surface expression of vβ3 in human lung fibroblasts. TGFβ1-induced vβ3 expression was strongly adhesion-dependent and associated with increased focal adhesion kinase and c-Src kinase phosphorylation. Inhibition of β3 integrin activation by the Arg-Gly-Asp tripeptide motif-specific disintegrin echistatin or vβ3 blocking antibody prevented the increase in β3 but not β5 integrin expression. In addition, echistatin inhibited TGFβ1-induced p38 MAPK but not Smad3 activation. Furthermore, inhibition of the Src family kinases, but not focal adhesion kinase, completely abrogated TGFβ1-induced expression of vβ3 and p38 MAPK phosphorylation but not β5 integrin expression and Smad3 activation. The TGFβ1-induced vβ3 expression was blocked by pharmacologic and genetic inhibition of p38 MAPK- but not Smad2/3-, Sp1-, ERK-, phosphatidylinositol 3-kinase, and NF-B-dependent pathways. Our results demonstrate that TGFβ1 induces vβ3 integrin expression via a β3 integrin-, c-Src-, and p38 MAPK-dependent pathway. These data identify a novel mechanism for TGFβ1 signaling in human lung fibroblasts by which they may contribute to normal and pathological wound healing.

Received for publication, October 3, 2007 , and in revised form, March 17, 2008.

^* This work was supported by the British Columbia Lung Association, the Canadian Institutes of Health Research, The Wolfe and Gita Churg Foundation, and the National Health and Medical Research Council of Australia. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Experimental Procedures and Figs. 1S–5S.

¹ To whom correspondence should be addressed: St. Paul's Hospital, 1081 Burrard St., Vancouver, British Columbia V6Z 1Y6, Canada. Tel.: 604-682-2344 (Ext. 62217); Fax: 604-806-9274; E-mail: dknight{at}mrl.ubc.ca.

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