title: Focal Adhesion Kinase Regulates Fibroblast Migration via Integrin beta-1 and Plays a Central Role in Fibrosis.
abstract: Lung fibrosis is a major medical problem for the aging population worldwide. Fibroblast migration plays an important role in fibrosis. Focal Adhesion Kinase (FAK) senses the extracellular stimuli and initiates signaling cascades that promote cell migration. This study first examined the dose and time responses of FAK activation in human lung fibroblasts treated with platelet derived growth factor BB (PDGF-BB). The data indicate that FAK is directly recruited by integrin β1 and the subsequent FAK activation is required for fibroblast migration on fibronectin. In addition, the study has identified that α5β1 and α4β1 are the major integrins for FAK-mediated fibroblast migration on fibronect. In contrast, integrins αvβ3, αvβ6, and αvβ8 play a minor but distinct role in fibroblast migration on fibronectin. FAK inhibitor significantly reduces PDGF-BB stimulated fibroblast migration. Importantly, FAK inhibitor protects bleomycin-induced lung fibrosis in mice. FAK inhibitor blocks FAK activation and significantly reduces signaling cascade of fibroblast migration in bleomycin-challenged mice. Furthermore, FAK inhibitor decreases lung fibrotic score, collagen accumulation, fibronectin production, and myofibroblast differentiation in in bleomycin-challenged mice. These data demonstrate that FAK mediates fibroblast migration mainly via integrin β1. Furthermore, the findings suggest that targeting FAK signaling is an effective therapeutic strategy against fibrosis.
authors.affiliation: Department of Infectious Diseases, The Hospital Affiliated to Guizhou Medical University, Guiyang, Guizhou, China.
authors.forename: Xue-Ke
authors.initials: XK
authors.lastname: Zhao
authors.affiliation: Department of Infectious Diseases, the First Hospital Affiliated to Soochow University, Suzhou, Jiangsu, China.
authors.forename: Yiju
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Infectious Diseases, The Hospital Affiliated to Guizhou Medical University, Guiyang, Guizhou, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Liang Cheng
authors.affiliation: Prenatal Diagnostic Center, The Hospital Affiliated to Guizhou Medical University, Guiyang, Guizhou, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Infectious Diseases, The Hospital Affiliated to Guizhou Medical University, Guiyang, Guizhou, China.
authors.forename: Mao
authors.initials: M
authors.lastname: Mu
authors.affiliation: Department of Infectious Diseases, The Hospital Affiliated to Guizhou Medical University, Guiyang, Guizhou, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Infectious Diseases, The Hospital Affiliated to Guizhou Medical University, Guiyang, Guizhou, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Infectious Diseases, The Hospital Affiliated to Guizhou Medical University, Guiyang, Guizhou, China.
authors.forename: Baofang
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Infectious Diseases, The Hospital Affiliated to Guizhou Medical University, Guiyang, Guizhou, China.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Department of Infectious Diseases, The Hospital Affiliated to Guizhou Medical University, Guiyang, Guizhou, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Guo
authors.affiliation: Department of Infectious Diseases, The Hospital Affiliated to Guizhou Medical University, Guiyang, Guizhou, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Infectious Diseases, The Hospital Affiliated to Guizhou Medical University, Guiyang, Guizhou, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000077214:Becaplermin; D001761:Bleomycin / Q000009:adverse effects; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005355:Fibrosis / Q000378:metabolism* / Q000473:pathology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D019012:Integrin beta1 / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism; D051379:Mice; D058628:Myofibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology
chemical_list: D019012:Integrin beta1; D016023:Integrins; D047428:Protein Kinase Inhibitors; D020574:Proto-Oncogene Proteins c-sis; D001761:Bleomycin; D000077214:Becaplermin; D051416:Focal Adhesion Protein-Tyrosine Kinases