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

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, 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.

The interplay between Src family kinases and receptor tyrosine kinases

“…Fibroblasts stimulated with FGF-1 showed SFK-dependent tyrosine phosphorylation of cortactin (Zhan et al, 1993(Zhan et al, , 1994. Further, the SH2 domain of Src mediates its association with the activated FGF-1R, and stimulation of fibroblasts with FGF-1 results in enhanced SFK activity (LaVallee et al, 1998). Another study also reported SFK activation in response to FGF treatment of some cell types, but not all (Landgren et al, 1995).…”

The Nonreceptor Protein-tyrosine Kinase c-Fes Is Involved in Fibroblast Growth Factor-2-induced Chemotaxis of Murine Brain Capillary Endothelial Cells

“…These results suggest that c-Fes is activated by FGF-2 treatment and may function to transmit signals for growth or differentiation. (28,29). These results raised the possibility that Src family kinases may act as intermediates between the FGF receptor and activation of c-Fes downstream.…”

Soluble Jagged 1 Represses the Function of Its Transmembrane Form to Induce the Formation of the Src-dependent Chord-like Phenotype

“…Cells were made quiescent by incubating the confluent monolayer in Dulbecco's modified Eagle's medium containing 0.25% (v/v) bovine calf serum for 24 h and further stimulated for an additional 24 h by the addition of 10 g/ml heparin (The Upjohn Co.) and 10 ng/ml recombinant human FGF-1, prepared as previously described (26). Immunoprecipitation of cortactin was performed as described (27), and immunoblot analysis of total phosphotyrosine, total Src, and phosphotyrosine-specific Src (Tyr(P) 418 ) was carried out using antibodies from Upstate Biotechnology, Inc., Santa Cruz Biotechnology, and BioSource, International, respectively, following methods previously described (27). Pro-␣1(I) collagen (monoclonal antibody SP1.D8 from the Developmental Studies Hybridoma Bank, University of Iowa) and cortactin (28) immunoblot analyses used similar methods.…”