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FHL2 is a LIM domain protein that is able to form various protein complexes and regulate gene transcription. Recent findings showed that FHL2 is a potential tumor suppressor gene that was down-regulated in hepatocellular carcinoma. In the present study, microarray profiling of gene expression was performed to identify the genes regulated by FHL2 in mouse livers. The differentially expressed genes were further analyzed by bioinformatics tools including DAVID, KEGG, and STRING. Our data illustrate that FHL2 affects genes involved in various functions including signal transduction, responses to external stimulus, cancer-related pathways, cardiovascular function and regulation of actin cytoskeleton. Moreover, a network of differentially expressed genes identified in this study and known FHL2-interacting proteins was constructed. Then, genes identified by bioinformatics tools and most functional relevant to FHL2 were selected for further validation. Finally, the differential expression of Ar, Id3, Inhbe, Alas1, Bcl6, Ppar, Angptl4, and Erbb4 were confirmed by quantitative real-time PCR. In summary, we have established a database of genes that are potentially regulated by FHL2 and these genes should be future targets for the elucidation of functional roles of FHL2. J. Cell. Biochem. 115: 744-753, 2014. (c) 2013 Wiley Periodicals, Inc.

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 beta 1 (TGF beta 1), 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 TGF beta 1 was investigated. LX-2 HSC were transfected with AGAP2 siRNA and treated with TGF beta 1. AGAP2 knockdown prevented to some extent the proliferative and migratory TGF beta 1-induced capacities of LX-2 cells. An array focused on human fibrosis revealed that AGAP2 knockdown partially prevented TGF beta 1-mediated gene expression of the fibrogenic genes ACTA2, COL1A2, EDN1, INHBE, LOX, PDGFB, TGEB12, while favored the expression of CXCR4, IL1A, MMP1, MMP3 and MMP9 genes. Furthermore, TGF beta 1 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 TGF beta 1-receptor 2 (TGFR2) trafficking in U2OS cells, blocking its effective recycling to the membrane. AGAP2 silencing in LX-2 cells prevented the TGF beta 1-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 TGF beta 1 in LX-2 overexpressing AGAP2. In summary, the present work shows for the first time, that AGAP2 is a potential new target involved in TGF beta 1 signalling, contributing to the progression of hepatic fibrosis.