Focal Adhesion Kinase Regulates Fibroblast Migration via Integrin beta-1 and Plays a Central Role in Fibrosis

被引：105

作者：

Zhao, Xue-Ke ^{[1
]}

Cheng, Yiju ^{[2
]}

Cheng, Ming Liang ^{[1
]}

Yu, Lei ^{[3
]}

Mu, Mao ^{[1
]}

Li, Hong ^{[1
]}

Liu, Yang ^{[1
]}

Zhang, Baofang ^{[1
]}

Yao, Yumei ^{[1
]}

Guo, Hui ^{[1
]}

Wang, Rong ^{[1
]}

Zhang, Quan ^{[1
]}

机构：

[1] Guizhou Med Univ, Hosp, Dept Infect Dis, Guiyang, Guizhou, Peoples R China

[2] Soochow Univ, Hosp 1, Dept Infect Dis, Suzhou, Jiangsu, Peoples R China

[3] Guizhou Med Univ, Hosp, Prenatal Diagnost Ctr, Guiyang, Guizhou, Peoples R China

来源：

SCIENTIFIC REPORTS | 2016年 / 6卷

关键词：

PULMONARY-FIBROSIS; TYROSINE PHOSPHORYLATION; CELL-MATRIX; FAK; PROTEIN; OVEREXPRESSION; EXPRESSION; S100A4; RHO; RECRUITMENT;

D O I：

10.1038/srep19276

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 beta 1 and the subsequent FAK activation is required for fibroblast migration on fibronectin. In addition, the study has identified that alpha 5 beta 1 and alpha 4 beta 1 are the major integrins for FAK-mediated fibroblast migration on fibronect. In contrast, integrins alpha v beta 3, alpha v beta 6, and alpha v beta 8 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 beta 1. Furthermore, the findings suggest that targeting FAK signaling is an effective therapeutic strategy against fibrosis.

引用

页数：12