Role of AGAP2 in the profibrogenic effects induced by TGFβ in LX-2 hepatic stellate cells
| Autor: | Gloria Alvarez-Sola, Eduardo Ansorena, María J. Iraburu, Matías A. Avila, María J. López-Zabalza, Amaia Navarro-Corcuera, Juan J. Martinez-Irujo, Cristina Montiel-Duarte |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Receptor recycling Liver Cirrhosis Male Cell Survival medicine.medical_treatment Gene Expression Collagen Type I Cell Line Rats Sprague-Dawley Transforming Growth Factor beta1 03 medical and health sciences 0302 clinical medicine Cell Movement GTP-Binding Proteins medicine Hepatic Stellate Cells Gene silencing Animals Humans Molecular Biology Cell Proliferation Gene knockdown Chemistry GTPase-Activating Proteins Receptor Transforming Growth Factor-beta Type II Cell Biology Transfection Cell biology 030104 developmental biology Cytokine 030220 oncology & carcinogenesis Focal Adhesion Protein-Tyrosine Kinases Hepatic stellate cell Hepatic fibrosis Transforming growth factor |
| Zdroj: | Biochimica et biophysica acta. Molecular cell research. 1866(4) |
| ISSN: | 1879-2596 0167-4889 |
| Popis: | Liver damage induces hepatic stellate cells (HSC) activation, characterised by a fibrogenic, proliferative and migratory phenotype. Activated HSC are mainly regulated by transforming growth factor β 1 (TGFβ1), which increases the production of extracellular matrix proteins (e.g. collagen-I) promoting the progression of hepatic fibrosis. AGAP2 (ArfGAP with GTPase domain, ankyrin repeat and PH domain 2) is a GTPase/GTP-activating protein involved in the actin remodelling system and receptor recycling. In the present work the role of AGAP2 in human HSC in response to TGFβ1 was investigated. LX-2 HSC were transfected with AGAP2 siRNA and treated with TGFβ1. AGAP2 knockdown prevented to some extent the proliferative and migratory TGFβ1-induced capacities of LX-2 cells. An array focused on human fibrosis revealed that AGAP2 knockdown partially prevented TGFβ1-mediated gene expression of the fibrogenic genes ACTA2, COL1A2, EDN1, INHBE, LOX, PDGFB, TGFΒ12, while favored the expression of CXCR4, IL1A, MMP1, MMP3 and MMP9 genes. Furthermore, TGFβ1 induced AGAP2 promoter activation and its protein expression in LX-2. Moreover, AGAP2 protein levels were significantly increased in liver samples from rats with thioacetamide-induced fibrosis. In addition, AGAP2 silencing affected TGFβ1-receptor 2 (TGFR2) trafficking in U2OS cells, blocking its effective recycling to the membrane. AGAP2 silencing in LX-2 cells prevented the TGFβ1-induced increase of collagen-I protein levels, while its overexpression enhanced collagen-I protein expression in the presence or absence of the cytokine. AGAP2 overexpression also increased focal adhesion kinase (FAK) phosphorylated levels in LX-2 cells. FAK and MEK1 inhibitors prevented the increase of collagen-I expression caused by TGFβ1 in LX-2 overexpressing AGAP2. In summary, the present work shows for the first time, that AGAP2 is a potential new target involved in TGFβ1 signalling, contributing to the progression of hepatic fibrosis. |
| Databáze: | OpenAIRE |
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