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J. Biol. Chem., Vol. 283, Issue 40, 26839-26849, October 3, 2008

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Focal Adhesion Kinase (FAK)-related Non-kinase Inhibits Myofibroblast Differentiation through Differential MAPK Activation in a FAK-dependent Manner^*

Qiang Ding¹, Candece L. Gladson, Hongju Wu^¶, Haurko Hayasaka^||, and Mitchell A. Olman

From the Department of Medicine, Division of Pulmonary and Critical Care Medicine, Department of Pathology, and ^¶Division of Human Gene Therapy, University of Alabama at Birmingham, Birmingham, Alabama 35294, and the ^||Departments of Microbiology and Immunology, Osaka University, Yamada-oka, Suita 565-0871, Japan

Transforming growth factor (TGF)-β1 induces fibroblast transdifferentiation to myofibroblasts, a process that requires the involvement of integrin-mediated signaling and focal adhesion kinase (FAK). FAK-related non-kinase (FRNK) is known for its role in inhibiting integrin-mediated cell migration; however, its role in myofibroblast differentiation has not been defined. Here, we report that FRNK abrogates TGF-β1-induced myofibroblast differentiation in vitro and in vivo. TGF-β1 can induce -smooth muscle actin (-SMA) expression in the presence or absence of FAK; however, TGF-β1-induced -SMA expression is reduced (73%) in FAK-deficient fibroblasts. Although both ERK and p38 MAPK activation is required for maximal TGF-β1-induced -SMA expression, ERK is the major signaling intermediate in cells that express FAK. In contrast, p38 MAPK is the dominant mediator of TGF-β1-induced -SMA expression in FAK-deficient cells. FRNK overexpression blocks TGF-β1-induced ERK or p38 MAPK activation in the presence, and surprisingly, in the absence of FAK. The loss of FRNK was tested in vivo during experimentally induced pulmonary fibrosis in mice. FRNK knock-out mice have a greater increase in -SMA-expressing cells in response to a pulmonary fibrotic stimulus in vivo, as compared with congenic wild type mice. This is the first time that FRNK loss has been shown to modify the pathobiology in any animal disease model. Together, the data demonstrate that FRNK negatively regulates myofibroblast differentiation in vitro and in vivo. These data further suggest that modulation FRNK expression may be a novel avenue for therapeutic intervention in tissue fibrosis.

Received for publication, May 12, 2008 , and in revised form, July 24, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants HL085324 (to Q. D.) and HL58655 (to M. A. O.). This work was also supported by a grant from the American Heart Association (to Q. D.) and a Veterans Affairs merit award (to M. A. O.). 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.

¹ To whom correspondence should be addressed: Dept. of Medicine, Division of Pulmonary and Critical Care Medicine, University of Alabama at Birmingham, 1900 University Blvd., 422 THT, Birmingham, AL 35294. Tel.: 205-996-2512; Fax: 205-975-6970; E-mail: qding{at}uab.edu.

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