Comparison of the intracellular signaling responses by three chimeric fibroblast growth factor receptors in PC12 cells.
Stably transfected PC12 cell lines expressing similar amounts of chimeric receptors composed of the extracellular domain of the human platelet-derived growth factor (PDGF)beta receptor and the transmembrane and intracellular domains of the fibroblast growth factor receptors (FGFRs) 1, 3, and 4 undergo ligand-induced differentiation. The FGFR1 chimera (PFR1) is the most potent of the three, and PFR4 requires more frequent (every 24 hr) addition of ligand to maintain the response. Both PFR1 and -3 also show significant ligand-independent autophosphorylation but PFR4 does not. All of the chimeras activated phospholipase Cgamma, Shc, FGFR substrate (FRS)2, and the mitogen-activated protein kinases, ERK1 and 2. PFR4 was moderately weaker in stimulating these effects as well; PFR1 and -3 were comparable. None of the chimeras induced Sos association or were coprecipitated with Shc. Cotransfection of a dominant-negative Shc derivative, with tyrosine at 239, 240, and 317 replaced with phenylalanine, in the PFR-expressing cells was without effect on PDGF-induced neurite outgrowth. The same derivative substantially inhibited the response of these cells to NGF. These results indicate that FGFR1, 3, and 4 (i) are capable of signaling in a similar fashion; (ii) primarily use FRS2 and, perhaps, PLCgamma; and (iii) do not utilize Shc. The results also suggest that the principal difference between FGFR1, 3, and 4 is in the strength of the tyrosine kinase activity and that qualitative differences in signaling capacity are likely to be less important.
Raffioni
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S
Department of Physiology and Biophysics, College of Medicine, University of California, Irvine, CA 92697, USA.
Thomas
D
D
Foehr
E D
ED
Thompson
L M
LM
Bradshaw
R A
RA
D000818:Animals; D002454:Cell Differentiation; D005346:Fibroblast Growth Factors / Q000378:metabolism; D006801:Humans; D008024:Ligands; D016716:PC12 Cells; D010766:Phosphorylation; D051381:Rats; D020797:Receptor, Platelet-Derived Growth Factor beta; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism*; D017479:Receptors, Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection
D008024:Ligands; D017468:Receptors, Fibroblast Growth Factor; D011993:Recombinant Fusion Proteins; D005346:Fibroblast Growth Factors; D020797:Receptor, Platelet-Derived Growth Factor beta; D017479:Receptors, Platelet-Derived Growth Factor