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ERK5/BMK1 Is Indispensable for Optimal Colony-Stimulating Factor 1 (CSF-1)-Induced Proliferation in Macrophages in a Src-Dependent Fashion¹

Dipartimento di Patologia e Oncologia Sperimentali, Università degli Studi di Firenze, Florence, Italy

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- 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Ente Cassa di Risparmio di Firenze and Fondazione Cassa di Risparmio di Volterra. E.R. was supported by a fellowship from Associazione and Federazione Italiana per la Ricerca sul Cancro (AIRC/FIRC).

² Address correspondence and reprint requests to Dr. Elisabetta Rovida, Dipartimento di Patologia e Oncologia Sperimentali, Universita’ degli Studi di Firenze, Viale G.B. Morgagni 50, Florence I-50134, Italy. E-mail address: erovida{at}unifi.it

³ Abbreviations used in this paper: SFK, Src family kinase; EGF, epidermal growth factor; MEKK, MEK kinase; PKC, protein kinase C; PTP, protein tyrosine phosphatase; siRNA, small interfering RNA; TPA, 12-O-tetradecanoylphorbol-13-acetate.