Opposite effects of different doses of MCSF on ERK phosphorylation and cell proliferation in macrophages.
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.
Rovida
Elisabetta
E
Department of Experimental Pathology and Oncology, Università degli Studi di Firenze, Florence, Italy.
Baccarini
Manvela
M
Olivotto
Massimo
M
Dello Sbarba
Persio
P
D000818:Animals; D001152:Arsenicals / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D048369:MAP Kinase Kinase 1; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019319:Okadaic Acid / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051578:Proto-Oncogene Proteins c-fes; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
D001152:Arsenicals; D011518:Proto-Oncogene Proteins; D019319:Okadaic Acid; C020979:benzenearsonic acid; D016173:Macrophage Colony-Stimulating Factor; D011505:Protein-Tyrosine Kinases; C496645:FES protein, human; C496646:Fes protein, mouse; D051578:Proto-Oncogene Proteins c-fes; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; C482127:Map2k1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases