Signal transduction pathways triggered by fibroblast growth factor receptor 1 expressed in Xenopus laevis oocytes after fibroblast growth factor 1 addition: Role of Grb2, phosphatidylinositol 3âkinase, Src tyrosine kinase, and phospholipase Cγ
2000
BrowaeysâPoly, Edith | Cailliau, Katia | Vilain, JeanâPierre
Xenopus oocytes expressing fibroblast growth factor receptor 1 (FGFR1) were used as a biological model system to analyse the signal transduction pathways that are triggered by fibroblast growth factor 1 (FGF1). Germinal vesicle breakdown (GVBD) and phosphorylation of extracellular signalâregulated protein kinase 2 (ERK2) occured 15âh after FGF1 addition. These events were Rasâdependent as they were blocked by a Ras dominant negative form. The Ras activity was promoted by three upstream effectors, growth factorâbound protein 2 (Grb2), phosphatidylinositol 3âkinase (PI3K) and Src cytoplasmic kinase. Ras activation was inhibited by a Grb2 dominant negative form (P49L), by PI3K inhibitors, including wortmannin, LY294002, the NâSH2 domain of p85α PI3K and by the SH2 domain of Src. Src activation induced by FGF1 was blocked by the SH2 domain of Src and PP2, a specific inhibitor of Src. The Grb2 adaptor was recruited by the upstream Src homology 2/αâcollagenârelated (Shc) effector, as the SH2âShc domain prevented the GVBD and the ERK2 phosphorylation induced by FGF1. The importance of another signalling pathway involving phospholipase Cγ (PLCγ) was also investigated. The use of the PLCγ inhibitory peptide, neomycin and the calcium chelator BAPTAâAM on oocytes expressing FGFR1 or the stimulation by PDGFâBB of oocytes expressing PDGFRâFGFR1 mutated on the PLCγ binding site, prevented GVBD and ERK2 phosphorylation. This study shows that the transduction cascade induced by the FGFR1–FGF1 interaction in Xenopus oocytes represents the sum of Rasâdependent and PLCγâdependent pathways. It emphasizes the role played by PI3K and Src and their connections with the Ras cascade in the FGFR1 signal transduction.
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