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 receptors and activation of kinase cascades leading to the expression of differentiation specific genes. We examined herein the hypothesis that FGF recep...

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Bibliographic Details
Published in:The Journal of biological chemistry 1999-07, Vol.274 (30), p.20901-20908
Main Authors: Chevet, Eric, Lemaı̂tre, Gilles, Janjić, Neboǰa, Barritault, Denis, Bikfalvi, Andreas, Katinka, Michaël Doron
Format: Article
Language:English
Subjects:
Animals
Cell Differentiation - drug effects
Cell Differentiation - physiology
Fibroblast Growth Factor 2 - pharmacology
Nerve Growth Factors - pharmacology
Neurites - ultrastructure
Neurons - cytology
Neurons - physiology
PC12 Cells
Protein Kinases - physiology
Rats
Receptors, Fibroblast Growth Factor - physiology
Signal Transduction - drug effects
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Summary: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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.274.30.20901