Cross talk among tyrosine kinase receptors in PC12 cells: desensitization of mitogenic epidermal growth factor receptors by the neurotrophic factors, nerve growth factor and basic fibroblast growth factor

I Mothe, R Ballotti, S Tartare, A Kowalski-Chauvel and E Van Obberghen

Institut National de la Sante et de la Recherche Medicale U 145, Faculte de Medecine, Nice, France.

We have studied the effects of nerve growth factor (NGF) and basic fibroblast growth factor (bFGF) on epidermal growth factor (EGF) binding to PC12 cells. We show that NGF and bFGF rapidly induce a reduction in 125I-EGF binding to PC12 cells in a dose-dependent manner. This decrease amounts to 50% for NGF and 35% for bFGF. Both factors appear to act through a protein kinase C(PKC)-independent pathway, because their effect persists in PKC-downregulated PC12 cells. Scatchard analysis indicates that NGF and bFGF decrease the number of high affinity EGF binding sites. In addition to their effect on EGF binding, NGF and bFGF activate in intact PC12 cells one or several serine/threonine kinases leading to EGF receptor threonine phosphorylation. Using an in vitro phosphorylation system, we show that NGF- or bFGF-activated extracellular regulated kinase 1 (ERK1) is able to phosphorylate a kinase-deficient EGF receptor. Phosphoamino acid analysis indicates that this phosphorylation occurs mainly on threonine residues. Furthermore, two comparable phosphopeptides are observed in the EGF receptor, phosphorylated either in vivo after NGF treatment or in a cell-free system by NGF-activated ERK1. Finally, a good correlation was found between the time courses of ERK1 activation and 125I-EGF binding inhibition after NGF or bFGF treatment. In conclusion, in PC12 cells the NGF- and bFGF-stimulated ERK1 appears to be involved in the induction of the threonine phosphorylation of the EGF receptor and the decrease in the number of high affinity EGF binding sites.

Volume 4, Issue 7, pp. 737-746, 07/01/1993
Copyright © 1993 by The American Society for Cell Biology

This article has been cited by other articles:

				B. Vincenzi, D. Santini, A. Russo, M. Silletta, M. Gavasci, F. Battistoni, G. Di Cuonzo, L. Rocci, N. Gebbia, and G. Tonini Angiogenesis modifications related with cetuximab plus irinotecan as anticancer treatment in advanced colorectal cancer patients Ann. Onc., May 1, 2006; 17(5): 835 - 841. [Abstract] [Full Text] [PDF]

				M. Gallicchio, S. Mitola, D. Valdembri, R. Fantozzi, B. Varnum, G. C. Avanzi, and F. Bussolino Inhibition of vascular endothelial growth factor receptor 2-mediated endothelial cell activation by Axl tyrosine kinase receptor Blood, March 1, 2005; 105(5): 1970 - 1976. [Abstract] [Full Text] [PDF]

				K. Ye, D. A. Compton, M. M. Lai, L. D. Walensky, and S. H. Snyder Protein 4.1N Binding to Nuclear Mitotic Apparatus Protein in PC12 Cells Mediates the Antiproliferative Actions of Nerve Growth Factor J. Neurosci., December 15, 1999; 19(24): 10747 - 10756. [Abstract] [Full Text] [PDF]

				P. Perrotte, T. Matsumoto, K. Inoue, H. Kuniyasu, B. Y. Eve, D. J. Hicklin, R. Radinsky, and C. P. N. Dinney Anti-epidermal Growth Factor Receptor Antibody C225 Inhibits Angiogenesis in Human Transitional Cell Carcinoma Growing Orthotopically in Nude Mice Clin. Cancer Res., February 1, 1999; 5(2): 257 - 264. [Abstract] [Full Text] [PDF]

				E. M. Mills, K. Takeda, Z.-X. Yu, V. Ferrans, Y. Katagiri, H. Jiang, M. C. Lavigne, T. L. Leto, and G. Guroff Nerve Growth Factor Treatment Prevents the Increase in Superoxide Produced by Epidermal Growth Factor in PC12 Cells J. Biol. Chem., August 28, 1998; 273(35): 22165 - 22168. [Abstract] [Full Text] [PDF]

				W. Englaro, C. Bertolotto, R. Busca, A. Brunet, G. Pages, J.-P. Ortonne, and R. Ballotti Inhibition of the Mitogen-activated Protein Kinase Pathway Triggers B16 Melanoma Cell Differentiation J. Biol. Chem., April 17, 1998; 273(16): 9966 - 9970. [Abstract] [Full Text] [PDF]

				M. Shibutani, P. Lazarovici, A. C. Johnson, Y. Katagiri, and G. Guroff Transcriptional Down-regulation of Epidermal Growth Factor Receptors by Nerve Growth Factor Treatment of PC12 Cells J. Biol. Chem., March 20, 1998; 273(12): 6878 - 6884. [Abstract] [Full Text] [PDF]

				V. J. Quijano Jr. and L. G. Sheffield Prolactin Decreases Epidermal Growth Factor Receptor Kinase Activity via a Phosphorylation-dependent Mechanism J. Biol. Chem., January 9, 1998; 273(2): 1200 - 1207. [Abstract] [Full Text] [PDF]

				P. Lazarovici, M. Oshima, D. Shavit, M. Shibutani, H. Jiang, M. Monshipouri, D. Fink, V. Movsesyan, and G. Guroff Down-regulation of Epidermal Growth Factor Receptors by Nerve Growth Factor in PC12 Cells Is p140trk-, Ras-, and Src-dependent J. Biol. Chem., April 25, 1997; 272(17): 11026 - 11034. [Abstract] [Full Text] [PDF]

				F. Renaud, S. Desset, L. Oliver, G. Gimenez-Gallego, E. Van Obberghen, Y. Courtois, and M. Laurent The Neurotrophic Activity of Fibroblast Growth Factor 1 (FGF1) Depends on Endogenous FGF1 Expression and Is Independent of the Mitogen-activated Protein Kinase Cascade Pathway J. Biol. Chem., February 2, 1996; 271(5): 2801 - 2811. [Abstract] [Full Text] [PDF]