FAK-related nonkinase is a multifunctional negative regulator of pulmonary fibrosis

Am J Pathol. 2013 May;182(5):1572-84. doi: 10.1016/j.ajpath.2013.01.026. Epub 2013 Mar 14.


Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease whose underlying molecular mechanisms are largely unknown. Herein, we show that focal adhesion kinase-related nonkinase (FRNK) plays a key role in limiting the development of lung fibrosis. Loss of FRNK function in vivo leads to increased lung fibrosis in an experimental mouse model. The increase in lung fibrosis is confirmed at the histological, biochemical, and physiological levels. Concordantly, loss of FRNK function results in increased fibroblast migration and myofibroblast differentiation and activation of signaling proteins that drive these phenotypes. FRNK-deficient murine lung fibroblasts also have an increased capacity to produce and contract matrix proteins. Restoration of FRNK expression in vivo and in vitro reverses these profibrotic phenotypes. These data demonstrate the multiple antifibrotic actions of FRNK. More important, FRNK expression is down-regulated in human IPF, and down-regulation of FRNK in normal human lung fibroblasts recapitulates the profibrotic phenotype seen in FRNK-deficient cells. The effect of loss and gain of FRNK in the experimental model, when taken together with its down-regulation in human IPF, suggests that FRNK acts as an endogenous negative regulator of lung fibrosis by repressing multiple profibrotic responses.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Animals
  • Bleomycin
  • Cell Differentiation / drug effects
  • Cell Movement / drug effects
  • Down-Regulation / drug effects
  • Enzyme Activation / drug effects
  • Focal Adhesion Kinase 1 / metabolism
  • Humans
  • Lung / drug effects
  • Lung / enzymology
  • Lung / pathology
  • Mice
  • Mice, Inbred C57BL
  • Myofibroblasts / drug effects
  • Myofibroblasts / enzymology
  • Myofibroblasts / pathology
  • Protein-Tyrosine Kinases / deficiency
  • Protein-Tyrosine Kinases / metabolism*
  • Pulmonary Fibrosis / enzymology*
  • Pulmonary Fibrosis / pathology*
  • Signal Transduction / drug effects
  • Transforming Growth Factor beta1 / pharmacology


  • Transforming Growth Factor beta1
  • Bleomycin
  • FAK-related nonkinase
  • Protein-Tyrosine Kinases
  • Focal Adhesion Kinase 1