ERK5 differentially regulates PDGF-induced proliferation and migration of hepatic stellate cells.
OBJECTIVE
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.
Rovida
Elisabetta
E
Dipartimento di Patologia e Oncologia Sperimentali, University of Florence, Italy.
Navari
Nadia
N
Caligiuri
Alessandra
A
Dello Sbarba
Persio
P
Marra
Fabio
F
D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005455:Fluorescent Antibody Technique; D006801:Humans; D008099:Liver / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D048054:Mitogen-Activated Protein Kinase 7 / Q000502:physiology*; D020286:Pericytes / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D034741:RNA, Small Interfering; D013347:Subcellular Fractions / Q000378:metabolism
D010982:Platelet-Derived Growth Factor; D034741:RNA, Small Interfering; D048054:Mitogen-Activated Protein Kinase 7