Abstract
Focal adhesion kinase (FAK) is an important mediator of extracellular matrix–integrin mechano-signal transduction that regulates cell motility, survival, and proliferation. As such, FAK is being investigated as a potential therapeutic target for malignant and fibrotic diseases, and numerous clinical trials of FAK inhibitors are underway. The function of FAK in nonmalignant, nonmotile epithelial cells is not well understood. We previously showed that hepatocytes demonstrated activated FAK near stiff collagen tracts in fibrotic livers. In this study, we examined the role of liver epithelial FAK by inducing fibrotic liver disease in mice with liver epithelial FAK deficiency. We found that mice that lacked FAK in liver epithelial cells developed more severe liver injury and worse fibrosis as compared with controls. Increased fibrosis in liver epithelial FAK-deficient mice was linked to the activation of several profibrotic pathways, including the hedgehog/smoothened pathway. FAK-deficient hepatocytes produced increased Indian hedgehog in a manner dependent on matrix stiffness. Furthermore, expression of the hedgehog receptor, smoothened, was increased in macrophages and biliary cells of hepatocyte-specific FAK-deficient fibrotic livers. These results indicate that liver epithelial FAK has important regulatory roles in the response to liver injury and progression of fibrosis.
Highlights
Mechano-signal transduction is the process through which physical stimuli are converted to biochemical signals within cells that orchestrate cell morphology and behavior
Differential gene expression analysis of whole-liver tissue or isolated hepatocytes from FAKfl/fl AlbCre+ compared with FAKfl/fl Alb-Cre– mice revealed 782 genes, which were hierarchically classified into 4 clusters based on expression pattern (Figure 1)
Clusters 1 and 2 represented genes that were downregulated in FAKfl/fl Alb-Cre+ liver and hepatocytes, whereas clusters 3 and 4 contained genes that were upregulated in FAKfl/fl Alb-Cre+ liver and hepatocytes
Summary
Mechano-signal transduction is the process through which physical stimuli are converted to biochemical signals within cells that orchestrate cell morphology and behavior. Through its dual function as a tyrosine kinase and scaffolding protein, FAK mediates signals triggered by integrin binding to extracellular matrix ligands and links integrin activation, via adaptor proteins, to actin cytoskeletal responses [2]. FAK broadly interacts with and cross-regulates other mechano-sensors and mediators of integrin signals, including Src [5, 6], Rho family GTPases [7, 8], integrin-linked kinase (ILK) [9, 10], and Yes-associated protein (YAP) [11, 12]. Stiffened tumor stroma activates FAK and downstream cell contractility, which cooperate with growth factor–mediated signals to potentiate proliferation and invasive behavior of malignant cells [7, 8]. Hepatocellular carcinoma is one cancer type that frequently demonstrates FAK overexpression and/or hyperphosphorylation [14]. Numerous FAK-specific small-molecule inhibitors have been developed [18], and several ongoing clinical trials are testing the safety and efficacy of FAK inhibition in the treatment of aggressive solid tumors in humans [19, 20]
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