ERK5 differentially regulates PDGF-induced proliferation and migration of hepatic stellate cells

Background/Aims: Hepatic stellate cells (HSC) are liver-specific pericytes implicated in liver tissue repair. Activation of signaling pathways in HSC modulates hepatic fibrogenesis, but no information is available on the possible role of ERK5, a member of the mitogen-activated protein kinase family, in this process. In this study, we investigated the role of ERK5 in the biologic responses triggered by platelet-derived growth factor (PDGF) in HSC. Methods: Human HSC were cultured on plastic and studied in their myofibroblast-like phenotype. Results: PDGF-BB rapidly induced ERK5 activation and translocation to the nucleus. EGF and PDGF-DD were also found to activate ERK5. Interfering with Src activation blocked PDGF-BB-dependent ERK5 phosphorylation. To establish the biological significance of ERK5 activation, HSC were transfected with non-targeting siRNA or siRNA targeting ERK5. ERK5 silencing inhibited PDGF-BB-induced cell proliferation, and expression and activation of c-Jun. In contrast, depletion of ERK5 was associated with significantly increased cell migration, both in the presence or absence of PDGF-BB. This effect was associated with a redistribution of focal contacts, and with decreased phosphorylation of FAK, paxillin, and PAK. Conclusions: ERK5 modulates PDGF-dependent biologic activities in human HSC, generating positive signals for cell proliferation downregulating the ability of the cells to migrate. (c) 2007 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.