Focal Adhesion Kinase Regulates Hepatic Stellate Cell Activation and Liver Fibrosis

Zhao, Xueke; Li, Yu; Cheng, Mingliang; Che, Pulin; Lu, Yinying; Zhang, Quan; Mu, Mao; Li, Hong; Zhu, Lili; Zhu, Juanjuan; Meng, Heng; Li, Po; Liang, Yuedong; Luo, Xin; Cheng, Yiju; Xu, Zhi‐Xiang; Ding, Qiang

doi:10.1038/s41598-017-04317-0

Cited by 96 publications

(78 citation statements)

References 69 publications

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“…GSEA in samples with low MPI , regardless of level of fibrosis, revealed cell and focal adhesion clusters to be consistently ranked first among the gene sets significantly enriched in these samples across data sets (Fig. C; Supporting Table ), a finding consistent with deranged cell adhesion as a hallmark of liver fibrosis . These data demonstrate an inverse correlation between MPI gene expression and fibrosis in adult human liver disease.…”

Section: Resultssupporting

confidence: 53%

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Mannose Phosphate Isomerase and Mannose Regulate Hepatic Stellate Cell Activation and Fibrosis in Zebrafish and Humans

et al. 2019

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The growing burden of liver fibrosis and lack of effective antifibrotic therapies highlight the need for identification of pathways and complementary model systems of hepatic fibrosis. A rare, monogenic disorder in which children with mutations in mannose phosphate isomerase (MPI) develop liver fibrosis led us to explore the function of MPI and mannose metabolism in liver development and adult liver diseases. Herein, analyses of transcriptomic data from three human liver cohorts demonstrate that MPI gene expression is down‐regulated proportionate to fibrosis in chronic liver diseases, including nonalcoholic fatty liver disease and hepatitis B virus. Depletion of MPI in zebrafish liver in vivo and in human hepatic stellate cell (HSC) lines in culture activates fibrotic responses, indicating that loss of MPI promotes HSC activation. We further demonstrate that mannose supplementation can attenuate HSC activation, leading to reduced fibrogenic activation in zebrafish, culture‐activated HSCs, and in ethanol‐activated HSCs. Conclusion: These data indicate the prospect that modulation of mannose metabolism pathways could reduce HSC activation and improve hepatic fibrosis.

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Section: Resultssupporting

confidence: 53%

“…1C; Supporting Table S3), a finding consistent with deranged cell adhesion as a hallmark of liver fibrosis. (22) These data demonstrate an inverse correlation between MPI gene expression and fibrosis in adult human liver disease.…”

Section: Mpi Expression Is Inversely Correlated With Advanced Fibrosimentioning

confidence: 74%

Mannose Phosphate Isomerase and Mannose Regulate Hepatic Stellate Cell Activation and Fibrosis in Zebrafish and Humans

et al. 2019

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“…Crosstalk has been reported between the TGFb signaling pathway and the following pathways: MAPK, TNF, and FoxO (51)(52)(53). Associations of TGFb with hypertrophic cardiomyopathy, dilated cardiomyopathy, proteoglycans in cancer, focal adhesion, HIF1 signaling pathway, and Rap1 signaling have also been reported (54)(55)(56)(57)(58)(59). Therefore, the results of pathway analysis of TGFb targets are appropriate, as these are similar to previous reports.…”

Section: Discussionsupporting

confidence: 72%

Long Noncoding RNA ELIT-1 Acts as a Smad3 Cofactor to Facilitate TGFβ/Smad Signaling and Promote Epithelial–Mesenchymal Transition

et al. 2019

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“…Phosphorylation and the activity of FAK were up‐regulated in scleroderma dermal fibroblasts and fibroblasts of lung fibrosis patients . It has been shown that at the downstream of platelet‐derived growth factor and TGFβ receptors, FAK transmits signals to Akt, ERK, and p38 mitogen‐activated protein kinase (MAPK) pathways that contribute to HSC activation and liver fibrosis . However, it is unknown whether FAK in return modulates TGFβ receptors.…”

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confidence: 99%

Focal Adhesion Kinase Promotes Hepatic Stellate Cell Activation by Regulating Plasma Membrane Localization of TGFβ Receptor 2

Chen

et al. 2019

Hepatol Commun

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Transforming growth factor β (TGFβ) induces hepatic stellate cell (HSC) differentiation into tumor-promoting myofibroblast, although underlying mechanism remains incompletely understood. Focal adhesion kinase (FAK) is activated in response to TGFβ stimulation, so it transmits TGFβ stimulus to extracellular signal-regulated kinase and P38 mitogenactivated protein kinase signaling. However, it is unknown whether FAK can, in return, modulate TGFβ receptors. In this study, we tested whether FAK phosphorylated TGFβ receptor 2 (TGFβR2) and regulated TGFβR2 intracellular trafficking in HSCs. The FAKY397F mutant and PF-573,228 were used to inhibit the kinase activity of FAK, the TGFβR2 protein level was quantitated by immunoblotting, and HSC differentiation into myofibroblast was assessed by expression of HSC activation markers, alpha-smooth muscle actin, fibronectin, or connective tissue growth factor. We found that targeting FAK kinase activity suppressed the TGFβR2 protein level, TGFβ1-induced mothers against decapentaplegic homolog phosphorylation, and myofibroblastic activation of HSCs. At the molecular and cellular level, active FAK (phosphorylated FAK at tyrosine 397) bound to TGFβR2 and kept TGFβR2 at the peripheral plasma membrane of HSCs, and it induced TGFβR2 phosphorylation at tyrosine 336. In contrast, targeting FAK or mutating Y336 to F on TGFβR2 led to lysosomal sorting and degradation of TGFβR2. Using RNA sequencing, we identified that the transcripts of 764 TGFβ target genes were influenced by FAK inhibition, and that through FAK, TGFβ1 stimulated HSCs to produce a panel of tumor-promoting factors, including extracellular matrix remodeling proteins, growth factors and cytokines, and immune checkpoint molecule PD-L1. Functionally, targeting FAK inhibited tumorpromoting effects of HSCs in vitro and in a tumor implantation mouse model. Conclusion: FAK targets TGFβR2 to the plasma membrane and protects TGFβR2 from lysosome-mediated degradation, thereby promoting TGFβ-mediated HSC activation. FAK is a target for suppressing HSC activation and the hepatic tumor microenvironment. (Hepatology Communications 2020;4:268-283).269 express α-smooth muscle actin (α-SMA), fibronectin and connective tissue growth factor (CTGF), markers of HSC activation, (4,5) and paracrine factors that promote liver metastatic growth. (6) Understanding how TGFβ signaling events are regulated, such as how TGFβ receptors distribute and traffic in HSCs, will help identify targets to inhibit HSC activation and the metastasis-promoting liver microenvironment.Focal adhesion kinase (FAK) is a 125-kDa nonreceptor tyrosine (Y) kinase. It consists of an N-terminal FERM domain, a middle kinase domain, and a C-terminal FAT domain. (7,8) Inactive FAK exists as an auto-inhibited monomer, and its autophosphorylation at Y397 creates a binding site for SH2 domain of Src, so that Src is recruited to induce phosphorylation of FAK at additional sites, leading to full activation of FAK kinase. (7,8) In addition, FAK functions as a protein scaffold for sign...

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Focal Adhesion Kinase Regulates Hepatic Stellate Cell Activation and Liver Fibrosis

Cited by 96 publications

References 69 publications

Mannose Phosphate Isomerase and Mannose Regulate Hepatic Stellate Cell Activation and Fibrosis in Zebrafish and Humans

Mannose Phosphate Isomerase and Mannose Regulate Hepatic Stellate Cell Activation and Fibrosis in Zebrafish and Humans

Long Noncoding RNA ELIT-1 Acts as a Smad3 Cofactor to Facilitate TGFβ/Smad Signaling and Promote Epithelial–Mesenchymal Transition

Focal Adhesion Kinase Promotes Hepatic Stellate Cell Activation by Regulating Plasma Membrane Localization of TGFβ Receptor 2

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