J Biol Chem, Vol. 274, Issue 30, 20901-20908, July 23, 1999

Fibroblast Growth Factor Receptors Participate in the Control of Mitogen-activated Protein Kinase Activity during Nerve Growth Factor-induced Neuronal Differentiation of PC12 Cells

Eric Chevet, Gilles Lemaître, Neboa Janji^¶, Denis Barritault, Andreas Bikfalvi, and Michaël Doron Katinka

From the  Laboratoire CRRET, Université Paris XII-Val de Marne, 61, 94010 Créteil, France,  Growth Factor and Cell Differentiation Laboratory, University Bordeaux I, 33405 Talence, France, ^¶ NexStar Pharmaceuticals Inc., Boulder, Colorado 80301

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 receptors and activation of kinase cascades leading to the expression of differentiation specific genes. We examined herein the hypothesis that FGF receptors (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 FGFR-2 reduces NGF-induced neuritogenesis. Moreover, FGF-2 expression is modulated by NGF, and FGF-2 is detected at the cell surface. Oligonucleotides that specifically inhibit FGF-2 binding to its receptors are able to significantly reduce NGF-induced neurite outgrowth. Finally, the duration of mitogen-activated protein kinase (MAPK) activity upon FGF or NGF stimulation is shortened in FGFR-2 dominant negative cells through inactivation of signaling from the receptor to the Ras/MAPK pathway. In conclusion, these results demonstrate that FGFR activation is involved in neuritogenesis induced by NGF where it contributes to a sustained MAPK activity in response to NGF.