Downregulation of FAK-related non-kinase mediates the migratory phenotype of human fibrotic lung fibroblasts |
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Authors: | Guo-qiang Cai Anni Zheng Qingjiu Tang Eric S White Candece L Gladson Qiang Ding |
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Institution: | a Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, USA b Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, MI, USA c Department of Cancer Biology, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA d Department of Pathobiology, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA |
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Abstract: | Fibroblast migration plays an important role in the normal wound healing process; however, dysregulated cell migration may contribute to the progressive formation of fibrotic lesions in the diseased condition. To examine the role of focal-adhesion-kinase (FAK)-related non-kinase (FRNK) in regulation of fibrotic lung fibroblast migration, we examined cell migration, FRNK expression, and activation of focal adhesion kinase (FAK) and Rho GTPase (Rho and Rac) in primary lung fibroblasts derived from both idiopathic pulmonary fibrosis (IPF) patients and normal human controls. Fibrotic (IPF) lung fibroblasts have increased cell migration when compared to control human lung fibroblasts. FRNK expression is significantly reduced in IPF lung fibroblasts, while activation of FAK, Rho and Rac is increased in IPF lung fibroblasts. Endogenous FRNK expression is inversely correlated with FAK activation and cell migration rate in IPF lung fibroblasts. Forced exogenous FRNK expression abrogates the increased cell migration, and blocked the activation of FAK and Rho GTPase (Rho and Rac), in IPF lung fibroblasts. These data for the first time provide evidence that downregulation of endogenous FRNK plays a role in promoting cell migration through FAK and Rho GTPase in fibrotic IPF lung fibroblasts. |
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Keywords: | IPF idiopathic pulmonary fibrosis FAK focal adhesion kinase FRNK FAK-related non-kinase TGF-β1 transforming growth factor beta-1 Ad-FRNK adenoviral FRNK construct GFP green fluorescent protein PDGF-BB platelet derived growth factor BB MOI multiplicity of infection IP immunoprecipitate GEF guanine nucleotide exchange factor G3PDH glyceraldehyde 3-phosphate dehydrogenase HA Hemagglutinin epitope tag |
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