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Activation of the MAP kinase pathway by FGF-1 correlates with cell proliferation induction while activation of the
T M LaVallee1, I A Prudovsky, G A McMahon
1Department of Molecular Biology, Holland Laboratory, American Red Cross, Rockville, Maryland 20855, USA.
Abstract:
FGF regulates both cell migration and proliferation by receptor-dependent induction of immediate-early gene expression and tyrosine phosphorylation of intracellular polypeptides. Because little is known about the disparate nature of intracellular signaling pathways, which are able to discriminate between cell migration and proliferation, we used a washout strategy to examine the relationship between immediate-early gene expression and tyrosine phosphorylation with respect to the potential of cells either to migrate or to initiate DNA synthesis in response to FGF-1. We demonstrate that transient exposure to FGF-1 results in a significant decrease in Fos transcript expression and a decrease in tyrosine phosphorylation of the FGFR-1, p42(mapk), and p44(mapk). Consistent with these biochemical effects, we demonstrate that attenuation in the level of DNA synthesis such that a 1.5-h withdrawal is sufficient to return the population to a state similar to quiescence. In contrast, the level of Myc mRNA, the activity of Src, the tyrosine phosphorylation of cortactin, and the FGF-1-induced redistribution of cortactin and F-actin were unaffected by transient FGF-1 stimulation. These biochemical responses are consistent with an implied uncompromised migratory potential of the cells in response to growth factor withdrawal. These results suggest a correlation between Fos expression and the mitogen-activated protein kinase pathway with initiation of DNA synthesis and a correlation between high levels of Myc mRNA and Src kinase activity with the regulation of cell migration.
Insights
Fibroblast Growth Factor (FGF) signaling pathways differentially regulate cell migration and proliferation. Fos expression correlates with DNA synthesis, while Myc mRNA and Src kinase activity regulate cell migration.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Fibroblast Growth Factor (FGF) regulates cell migration and proliferation through receptor-dependent signaling.
- Intracellular signaling pathways that discriminate between migration and proliferation remain poorly understood.
Purpose of the Study:
- To investigate the relationship between immediate-early gene expression and tyrosine phosphorylation in FGF-1-induced cell migration and proliferation.
- To elucidate the distinct signaling mechanisms governing cell migration versus DNA synthesis.
Main Methods:
- Utilized a washout strategy to examine cellular responses to transient FGF-1 stimulation.
- Analyzed transcript expression (Fos, Myc), tyrosine phosphorylation (FGFR-1, p42(mapk), p44(mapk), cortactin), and kinase activity (Src).
- Assessed DNA synthesis and F-actin/cortactin redistribution.
Main Results:
- Transient FGF-1 exposure decreased Fos transcript and tyrosine phosphorylation of FGFR-1, p42(mapk), and p44(mapk), leading to attenuated DNA synthesis.
- Myc mRNA levels, Src kinase activity, and cortactin phosphorylation/redistribution remained unaffected by transient FGF-1 stimulation.
- These findings suggest distinct signaling pathways for proliferation and migration.
Conclusions:
- Fos expression and the mitogen-activated protein kinase pathway are correlated with the initiation of DNA synthesis.
- High Myc mRNA levels and Src kinase activity are correlated with the regulation of cell migration.
- FGF-1 signaling employs distinct molecular mechanisms to control cell proliferation and migration.