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© The Rockefeller University Press, 0021-9525/1998//1647 $5.00
The Journal of Cell Biology, Volume 141, Number 7, , 1998 1647-1658

Articles

Activation of the MAP Kinase Pathway by FGF-1 Correlates with Cell Proliferation Induction While Activation of the Src Pathway Correlates with Migration



Theresa M. LaVallee*, Igor A. Prudovsky{ddagger}, Grainne A. McMahon*, Xiaoguo Hu*, and Thomas Maciag{ddagger}

* Department of Molecular Biology, Holland Laboratory, American Red Cross, Rockville, Maryland 20855; and {ddagger} Center for Molecular Medicine, Maine Medical Center Research Institute, S. Portland, Maine 04106

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, p42mapk, and p44mapk. 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.

Abbreviations used in this paper: DMI, defined medium with insulin; FAK, focal adhesion kinase; FGFR, FGF receptor; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; MAP, mitogen-activated protein; MAPK, mitogen-activated protein kinase; ODC, ornithine decarboxylase.

T.M. LaVallee and I.A. Prudovsky contributed equally to the content of this manuscript. The present address of T.M. LaVallee is EntreMed, Inc., 9610 Medical Center Drive, Rockville, MD 20850.

Address all correspondence to Thomas Maciag, Center for Molecular Medicine, Maine Medical Center Research Institute, 125 John Roberts Road, S. Portland, ME 04106. Tel.: 207-761-9783; FAX: 207-828-9071.


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