Fibroblast growth factor receptors participate in the control of mitogen-activated protein kinase activity during nerve growth factor-induced neuronal differentiation of PC12 cells

The current paradigm for the role of nerve growth factor (NGF) or FGF-2 in the differentiation of neuronal cells implies their binding to specific rec eptors and activation of kinase cascades leading to the expression of diffe rentiation specific genes. We examined herein the hypothesis that FGF recep tors (FGFRs) are involved in NGF-induced neuritogenesis of pheochromocytoma -derived PC12 cells. We demonstrate that in PC12 cells, FGFR expression and activity are modulated upon NGF treatment and that a dominant negative FGF R-2 reduces NGF-induced neuritogenesis. Moreover, FGF-2 expression is modul ated by NGF, and FGF-2 is detected at the cell surface. Oligonucleotides th at specifically inhibit FGF-2 binding to its receptors are able to signific antly reduce NGF-induced neurite outgrowth. Finally, the duration of mitoge n-activated protein kinase (MAPK) activity upon FGF or NGF stimulation is s hortened in FGFR-2 dominant negative cells through inactivation of signalin g from the receptor to the Ras/MAPK pathway. In conclusion, these results d emonstrate that FGFR activation is involved in neuritogenesis induced by NG F where it contributes to a sustained MAPK activity in response to NGF.