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-γ 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.

Cell-specific translational profiling in acute kidney injury

“…ERK5 action underlies the CSF-1-induced proliferation of macrophages in vitro and is emerging as a key regulator of tumor cell invasion and migration (51)(52)(53). Interestingly, Csf1 is substantially elevated in the Foxd1-and Lyz2-derived cellular com- tion of cellular RNA.…”

ERK5 Protein Promotes, whereas MEK1 Protein Differentially Regulates, the Toll-like Receptor 2 Protein-dependent Activation of Human Endothelial Cells and Monocytes

“…The few published reports on the role of ERK5 in TLR-mediated signaling show conflicting results. For example, LPS has been reported to activate ERK5 in RAW264.7 macrophages but has also been reported to not activate ERK5 in BAC1.2F5 macrophages (29,53). However, ERK5 does have a critical role in EC biology (54).…”

Fibronectin induces macrophage migration through a SFK-FAK/CSF-1R pathway

“…Roussel, St. Jude Children's Research Hospital, Memphis, TN, USA) and J774 murine macrophage cell line, derived from a reticular cell sarcoma, were cultured in DMEM supplemented with 4 mM glutamine and 10 % FBS. 39 Primary human macrophages were obtained following differentiation of monocytes from peripheral blood of healthy donor after informed consent (and after approval of the project BIO 14.015 by the ethical committee of Azienda Ospedaliero-Universitaria di Careggi, Firenze, Italy; prot. no 2014/00 26551).…”