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The Proceedings of the American Thoracic Society 5:364 (2008)
© 2008 The American Thoracic Society
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Myofibroblast Differentiation Is Negatively Regulated by FAK-related Non-kinase

Qiang Ding1, Candece L. Gladson1, Hongjui Wu1 and Mitchell A. Olman1

1 Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama

Correspondence and requests for reprints should be addressed to Qiang (John) Ding, Ph.D., Assistant Professor of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, 437 THT, 1900 University Boulevard, Birmingham, AL 35294. E-mail: qding{at}uab.edu

Myofibroblast differentiation from fibroblasts has been hypothesized to be an important pro-fibrotic mechanism after lung injury. Focal adhesion kinase (FAK) is a pleiotropic non–receptor tyrosine kinase that mediates TGF-β1–induced myofibroblast differentiation. However, the role of FAK-related non-kinase (FRNK), a naturally occurring inhibitor of FAK signaling, in myofibroblast differentiation is unknown. The effect of FRNK overexpression and pharmacologic inhibition of mitogen-activated protein kinase (MAPK) signaling on TGF-β1–induced myofibroblast differentiation ({alpha}-smooth muscle actin [{alpha}-SMA]) expression was examined in fibroblasts that either express or lack FAK. FRNK overexpression abrogates TGF-β1–induced {alpha}-SMA expression and MAPK (ERK and p38) activation in lung fibroblasts. In fibroblasts expressing FAK, TGF-β1 induces both ERK and p38 activation, and both ERK and p38 are required for TGF-β1–induced {alpha}-SMA expression. In contrast, in fibroblasts lacking FAK, TGF-β1 induction of {alpha}-SMA expression is independent of ERK, but dependent only on p38 activation. These results demonstrate that (1) FRNK inhibits TGF-β1–induced myofibroblast differentiation through both FAK-dependent and FAK-independent pathways; and (2) both ERK and p38 MAPKs are downstream mediators in the FAK-dependent pathway, while only p38 MAPK is a downstream mediator in the FAK-independent pathway. These data delineate the role of FRNK and MAPK signaling pathways in myofibroblast differentiation, and suggest that FRNK could be a negative regulator of myofibroblast differentiation during the fibrotic process.

FOOTNOTES

Funded by NIH grants HL085324 (Q.D.) and HL58655 (M.A.O.), AHA, and VA MERIT Review Board.

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form August 31, 2007; accepted in final form October 16, 2007)





This Article
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Right arrow Articles by Ding, Q.
Right arrow Articles by Olman, M. A.

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