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Mol Cell Biol, July 1998, p. 3762-3770, Vol. 18, No. 7
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Identification of the Cytoplasmic Regions of Fibroblast Growth Factor (FGF) Receptor 1 Which Play Important Roles in Induction of Neurite Outgrowth in PC12 Cells by FGF-1

Hsien-Yi Lin,1 dagger Jingsong Xu,2 Irene Ischenko,3 David M. Ornitz,2 Simon Halegoua,4 and Michael J. Hayman3 *

Graduate Program in Molecular Biology and Biochemistry,1 Department of Molecular Genetics and Microbiology,3 and Department of Neurobiology and Behavior,4 Institute of Cell and Developmental Biology, State University of New York at Stony Brook, Stony Brook, New York 11794, and Department of Molecular Biology and Pharmacology, Washington University Medical School, St. Louis, Missouri 63110-81032

Received 11 November 1997/Returned for modification 24 December 1997/Accepted 14 April 1998

Fibroblast growth factor 1 (FGF-1) induces neurite outgrowth in PC12 cells. Recently, we have shown that the FGF receptor 1 (FGFR-1) is much more potent than FGFR-3 in induction of neurite outgrowth. To identify the cytoplasmic regions of FGFR-1 that are responsible for the induction of neurite outgrowth in PC12 cells, we took advantage of this difference and prepared receptor chimeras containing different regions of the FGFR-1 introduced into the FGFR-3 protein. The chimeric receptors were introduced into FGF-nonresponsive variant PC12 cells (fnr-PC12 cells), and their ability to mediate FGF-stimulated neurite outgrowth of the cells was assessed. The juxtamembrane (JM) and carboxy-terminal (COOH) regions of FGFR-1 were identified as conferring robust and moderate abilities, respectively, for induction of neurite outgrowth to FGFR-3. Analysis of FGF-stimulated activation of signal transduction revealed that the JM region of FGFR-1 conferred strong and sustained tyrosine phosphorylation of several cellular proteins and activation of MAP kinase. The SNT/FRS2 protein was demonstrated to be one of the cellular substrates preferentially phosphorylated by chimeras containing the JM domain of FGFR-1. SNT/FRS2 links FGF signaling to the MAP kinase pathway. Thus, the ability of FGFR-1 JM domain chimeras to induce strong sustained phosphorylation of this protein would explain the ability of these chimeras to activate MAP kinase and hence neurite outgrowth. The role of the COOH region of FGFR-1 in induction of neurite outgrowth involved the tyrosine residue at amino acid position 764, a site required for phospholipase C gamma binding and activation, whereas the JM region functioned primarily through a non-phosphotyrosine-dependent mechanism. In contrast, assessment of the chimeras in the pre-B lymphoid cell line BaF3 for FGF-1-induced mitogenesis revealed that the JM region did not play a role in this cell type. These data indicate that FGFR signaling can be regulated at the level of intracellular interactions and that signaling pathways for neurite outgrowth and mitogenesis use different regions of the FGFR.

* Corresponding author. Mailing address: Department of Molecular Genetics and Microbiology, Institute of Cell and Developmental Biology, State University of New York at Stony Brook, Stony Brook, NY 11794. Phone: (516) 632-8792. Fax: (516) 632-8891. E-mail: hayman{at}asterix.bio.sunysb.edu.

dagger Present address: Department of Molecular Biology, Princeton University, Princeton, NJ 08544-1014.

Mol Cell Biol, July 1998, p. 3762-3770, Vol. 18, No. 7
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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