Abstract
We had previously shown that murine macrophages expressing v-Fes, the oncogenically activated counterpart of the c-Fes cytoplasmic tyrosine kinase, proliferate independently of Macrophage Colony-Stimulating Factor (MCSF) and that the Extracellular signal-Regulated Kinase (ERK) pathway mediates the mitogenic effect of v-Fes. In this study, the response of c-fes- and v-fes-overexpressing cells to MCSF was investigated. A critical modulation of the activation of Mitogen-activated ERK Kinase (MEK) and ERK based on the MCSF dose was characterized. ERK activation was increased by MCSF doses capable to elicit a mitogenic response (2–5 U/ml). On the contrary, MCSF doses as low as 0.05 U/ml markedly reduced ERK phosphorylation and nuclear content and moderately but significantly reduced cell proliferation. The reduction of MEK and ERK phosphorylation was very rapid, suggesting the involvement of cytosolic phosphatases. Among these, phospho–tyrosine protein phosphatases and phosphoserine/threonine protein phosphatase-2A were found involved. These findings represent the first observation that different doses of the same growth factor, MCSF in particular, can exert opposite effects on cell proliferation by switching on or off ERK signaling.
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Acknowledgements
The authors thanks Dr M Balzi and Dr P Cirri for cytofluorimetry. This work was funded by Associazione Italiana per la Ricerca sul Cancro (AIRC), Ministero della Università e della Ricerca Scientifica e Tecnologica and Ente Cassa di Risparmio di Firenze. E Rovida was supported by a fellowship from Fondazione Italiana per la Ricerca sul Cancro (FIRC).
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Rovida, E., Baccarini, M., Olivotto, M. et al. Opposite effects of different doses of MCSF on ERK phosphorylation and cell proliferation in macrophages. Oncogene 21, 3670–3676 (2002). https://doi.org/10.1038/sj.onc.1205409
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DOI: https://doi.org/10.1038/sj.onc.1205409
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