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.

PTEN improve renal fibrosis in vitro and in vivo through inhibiting FAK/AKT signaling pathway

“…As a cytoplasmic protein tyrosine kinase, FAK serves as a key factor in the process of embryo development and in the pathogenesis of human diseases, such as cancer, cardiovascular diseases, and fibrosis . FAK has been found to be expressed in the majority of tissues and its sequence is high conservation among species.…”

Targeting the complexity of Src signalling in the tumour microenvironment of pancreatic cancer: from mechanism to therapy

“…The mechanisms involved are complex but often include the regulation of downstream effectors, including TGFb, as well as regulators of ERK, Jun kinase (JNK) and Rho signalling pathways [34,35,42,[77][78][79]. It has recently been shown that FAK plays an important role in regulating pro-inflammatory pathway activation and cytokine production during wound healing [25,44,[80][81][82][83]. It has recently been shown that FAK plays an important role in regulating pro-inflammatory pathway activation and cytokine production during wound healing [25,44,[80][81][82][83].…”

Targeting Mechanotransduction at the Transcriptional Level: YAP and BRD4 Are Novel Therapeutic Targets for the Reversal of Liver Fibrosis

“…Indeed, several integrin-associated signaling proteins, including integrin-linked kinase (ILK, Zhang et al, 2006; Li et al, 2009; Kavvadas et al, 2010; Shafiei and Rockey, 2012; Radovanac et al, 2013), focal adhesion kinase (FAK, Wong et al, 2011; Lagares et al, 2012; Kinoshita et al, 2013; Lagares and Kapoor, 2013; Zhao et al, 2016), and regulators and effectors of Rho GTPases, such as P-Rex1 (Liang et al, 2016), PAK and Rho-activated kinase (ROCK, Knipe et al, 2015; Martin et al, 2016) have been identified as potential targets for anti-fibrotic therapy in a number of organs. Notably, activation of ILK, which links F-actin to focal adhesions and is required for integrin-mediated force generation, sustains nuclear YAP accumulation in pulmonary arterial vascular smooth muscle cells to promote cell proliferation in pulmonary arterial hypertension, a disease characterized by increased deposition of extracellular matrix and vascular stiffness (Kudryashova et al, 2016).…”