Role of AGAP2 in the profibrogenic effects induced by TGFβ in LX-2 hepatic stellate cells

Navarro-Corcuera, A., López-Zabalza, M.J., Martínez-Irujo, J.J., Álvarez-Sola, G., Ávila, M.A., Iraburu, M.J., Ansorena, E. and Montiel-Duarte, C. ORCID: 0000-0002-9144-8809, 2019. Role of AGAP2 in the profibrogenic effects induced by TGFβ in LX-2 hepatic stellate cells. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1866 (4), pp. 673-685. ISSN 0167-4889

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Abstract

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. 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 over-expression 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.

Item Type: Journal article
Publication Title: Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
Creators: Navarro-Corcuera, A., López-Zabalza, M.J., Martínez-Irujo, J.J., Álvarez-Sola, G., Ávila, M.A., Iraburu, M.J., Ansorena, E. and Montiel-Duarte, C.
Publisher: Elsevier
Date: 2019
Volume: 1866
Number: 4
ISSN: 0167-4889
Identifiers:
NumberType
10.1016/j.bbamcr.2019.01.008DOI
S0167488918304105Publisher Item Identifier
Divisions: Schools > School of Science and Technology
Depositing User: Linda Sullivan
Date Added: 18 Jan 2019 09:56
Last Modified: 12 Mar 2019 13:14
URI: http://irep.ntu.ac.uk/id/eprint/35609

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