Integrin αVβ1 Regulates Procollagen I Production through a Non-canonical Transforming Growth Factor β Signaling Pathway in Human Hepatic Stellate Cells

Biochem J. 2021 Apr 20:BCJ20200749. doi: 10.1042/BCJ20200749. Online ahead of print.ABSTRACTHepatic stellate cells (HSCs) are thought to play key roles in the development of liver fibrosis. Extensive evidence has established the concept that αV integrins are involved in the activation of latent transforming growth factor β (TGF-β), a master regulator of the fibrotic signaling cascade. Based on mRNA and protein expression profiling data, we found that αVβ1 integrin is the most abundant member of the αV integrin family in either quiescent or TGF-β1-activated primary human HSCs. Unexpectedly, either a selective αVβ1 inhibitor, Compound 8 (C8), or a pan-αV integrin inhibitor, GSK3008348, decreased TGF-β1-activated procollagen I production in primary human HSCs, in which the role of β1 integrin was confirmed by ITGB1 siRNA. In contrast to an Activin receptor-like kinase 5 (Alk5) inhibitor, C8 and GSK3008348 failed to inhibit TGF-β1 induced SMAD3 and SMAD2 phosphorylation, but inhibited TGF-β-induced phosphorylation of ERK1/2 and STAT3, suggesting that αVβ1 integrin is involved in non-canonical TGF-β signaling pathways. Consistently, ITGB1 siRNA significantly decreased phosphorylation of ERK1/2. Furthermore, a selective inhibitor of MEK1/2 blocked TGF-β1 induced phosphorylation of ERK1/2 and decreased TGF-β1 induced procollagen I production, while a specific inhibitor of STAT3 had no effect on TGF-β1 induced procollagen I production. Taken together, current data...
Source: The Biochemical Journal - Category: Biochemistry Authors: Source Type: research