ACTIVATION OF THE MAP KINASE PATHWAY BY FGF-1 CORRELATES WITH CELL-PROLIFERATION INDUCTION WHILE ACTIVATION OF THE SRC PATHWAY CORRELATES WITH MIGRATION

FGF regulates both cell migration and proliferation by receptor-depend ent induction of immediate-early gene expression and tyrosine phosphor ylation of intracellular polypeptides, Because little is known about t he disparate nature of intracellular signaling pathways, which are abl e to discriminate between cell migration and proliferation, we used a washout strategy to examine the relationship between immediate-early g ene expression and tyrosine phosphorylation with respect to the potent ial of cells either to migrate or to initiate DNA synthesis in respons e 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). Con sistent with these biochemical effects, we demonstrate that attenuatio n in the level of DNA synthesis such that a 1.5-h withdrawal is suffic ient to return the population to a state similar to quiescence. In con trast, the level of Myc mRNA, the activity of Src, the tyrosine phosph orylation of cortactin, and the FGF-1-induced redistribution of cortac tin and F-actin were unaffected by transient FGF-1 stimulation, These biochemical responses are consistent with an implied uncompromised mig ratory potential of the cells in response to growth factor withdrawal. These results suggest a correlation between Fos expression and the mi togen-activated protein kinase pathway with initiation of DNA synthesi s and a correlation between high levels of Myc mRNA and Src kinase act ivity with the regulation of cell migration.