title: ERK5/BMK1 is indispensable for optimal colony-stimulating factor 1 (CSF-1)-induced proliferation in macrophages in a Src-dependent fashion.
abstract: CSF-1, by binding to its high-affinity receptor CSF-1R, sustains the survival and proliferation of monocyte/macrophages, which are central cells of innate immunity and inflammation. The MAPK ERK5 (also known as big MAPK-1, BMK1, or MAPK7) is a 98-kDa molecule sharing high homology with ERK1/2. ERK5 is activated by oxidative stress or growth factor stimulation. This study was undertaken to characterize ERK5 involvement in macrophage signaling that is elicited by CSF-1. Exposure to the CSF-1 of primary human macrophages or murine macrophage cell lines, as well as murine fibroblasts expressing ectopic CSF-1R, resulted in a rapid and sustained increase of ERK5 phosphorylation on activation-specific residues. In the BAC1.2F5 macrophage cell line, ERK5 was also activated by another mitogen, GM-CSF, while macrophage activators such as LPS or IFN-gamma and a number of nonproliferative cytokines failed. Src family kinases were found to link the activation of CSF-1R to that of ERK5, whereas protein kinase C or the serine phosphatases PP1 and PP2A seem not to be involved in the process. Treatment of macrophages with ERK5-specific small interfering RNA markedly reduced CSF-1-induced DNA synthesis and total c-Jun phosphorylation and expression, while increasing the expression of the cyclin-dependent kinase inhibitor p27. Following CSF-1 treatment, the active form of ERK5 rapidly translocated from cytosol to nucleus. Taken together, the results reported in this study show that ERK5 is indispensable for optimal CSF-1-induced proliferation and indicate a novel target for its control.
authors.affiliation: Dipartimento di Patologia e Oncologia Sperimentali, Università degli Studi di Firenze, Florence, Italy. erovida@unifi.it
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Rovida
authors.forename: Elena
authors.initials: E
authors.lastname: Spinelli
authors.forename: Sara
authors.initials: S
authors.lastname: Sdelci
authors.forename: Valentina
authors.initials: V
authors.lastname: Barbetti
authors.forename: Andrea
authors.initials: A
authors.lastname: Morandi
authors.forename: Serena
authors.initials: S
authors.lastname: Giuntoli
authors.forename: Persio
authors.initials: P
authors.lastname: Dello Sbarba
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000502:physiology*; D008264:Macrophages / Q000166:cytology* / Q000201:enzymology* / Q000378:metabolism; D051379:Mice; D048054:Mitogen-Activated Protein Kinase 7 / Q000502:physiology*; D041681:NIH 3T3 Cells; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000502:physiology; D019061:src-Family Kinases / Q000502:physiology*
chemical_list: D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor; D019061:src-Family Kinases; D048054:Mitogen-Activated Protein Kinase 7