A novel role for farnesyl pyrophosphate synthase in fibroblast growth factor-mediated signal transduction.
Farnesyl pyrophosphate synthase (FPPS) catalyses the formation of a key cellular intermediate in isoprenoid metabolic pathways. Here we describe a novel role for this enzyme in fibroblast growth factor (FGF)-mediated signalling. We demonstrate the binding of FPPS to FGF receptors (FGFRs) using the yeast two-hybrid assay, pull-down assays and co-immunoprecipitation. The interaction between FPPS and FGFR is regulated by the cellular metabolic state and by treatment with FGF-2. Overexpression of FPPS inhibits FGF-2-induced cell proliferation, accompanied by a failure of the FGF-2-mediated induction of cyclins D1 and E. Overexpression of FPPS in fibroblasts also promotes increased farnesylation of Ras, and temporally extends FGF-2-stimulated activation of the Ras/ERK (extracellular-signal-regulated kinase) cascade. These data suggest that, in addition to its role in isoprenoid biosynthesis, FPPS may function as a modulator of the cellular response to FGF treatment.
Reilly
John F
JF
Department of Cell Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Martinez
Shawndra D
SD
Mickey
Gregory
G
Maher
Pamela A
PA
D016475:3T3 Cells; D019883:Alkyl and Aryl Transferases / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D005346:Fibroblast Growth Factors / Q000502:physiology*; D051228:Geranyltranstransferase; D007700:Kinetics; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000502:physiology; D011994:Recombinant Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D018631:ras Proteins / Q000378:metabolism
D018797:Cell Cycle Proteins; D017468:Receptors, Fibroblast Growth Factor; D011994:Recombinant Proteins; D016222:Fibroblast Growth Factor 2; D005346:Fibroblast Growth Factors; D019883:Alkyl and Aryl Transferases; D051228:Geranyltranstransferase; D019908:Proto-Oncogene Proteins c-raf; D018631:ras Proteins