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.
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.
Authors: George John Kastanis; Zamira Hernandez-Nazara; Natalia Nieto; Ana Rosa Rincón-Sanchez; Anastas Popratiloff; Jose Alfredo Dominguez-Rosales; Carmen G Lechuga; Marcos Rojkind Journal: Am J Physiol Gastrointest Liver Physiol Date: 2011-06-09 Impact factor: 4.052
Authors: Maria Radu; Karen Lyle; Klaus P Hoeflich; Olga Villamar-Cruz; Hartmut Koeppen; Jonathan Chernoff Journal: Mol Cell Biol Date: 2015-09-21 Impact factor: 4.272
Authors: Maria Irma Seixas Duarte; Heitor Franco de Andrade; Cleusa Fumica Hirata Takamura; Antonio Sesso; Felipe Francisco Tuon Journal: Parasitol Res Date: 2008-12-05 Impact factor: 2.289