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.
Abbreviations used: CD-R1, cytoplasmic domain of FGFR1; CKI, cyclin-dependent kinase inhibitor; DMEM, Dulbecco's modified Eagle's medium; ECL, enhanced chemiluminescence; EGF, epidermal growth factor; ERK, extracellular-signal-regulated kinase; FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; FPP, farnesyl pyrophosphate; FPPS, farnesyl pyrophosphate synthase; FRS2, FGF receptor substrate 2; FTase, farnesyl transferase; GAP, GTPase-activating protein; GST, glutathione S-transferase; MAP kinase, mitogen-activated protein kinase; MEK, MAP kinase/ERK kinase; PDGF, platelet-derived growth factor; RBD, Ras-binding domain.
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Nucleotide sequence data have been submitted to the GenBank®, DDBJ, EMBL and GSDB Nucleotide Sequence Databases under accession number AF309598.