Contribution of Src and Ras pathways in FGF-2 induced endothelial cell differentiation.
We have examined fibroblast growth factor (FGF) receptor-1 mediated signal transduction in differentiation of endothelial cells (EC). The activated FGFR-1 couples to Ras through two adaptor proteins, FRS2 and Shc. In FGF-2 treated proliferating EC, FRS2 as well as Shc are tyrosine phosphorylated and interact with Grb2. In contrast, in ... FGF-2 treated differentiating cells, Shc, but not FRS2, is engaged in Grb2-interactions. Sustained MAP kinase activity has previously been implicated in differentiation. In FGF stimulated proliferating and differentiating endothelial cells, the MAP kinase Erk2 is activated in a sustained manner. Inhibition of MEK and MAP kinase activity by PD98059 treatment of cells, still allows EC tube formation. The FGFR-1 mediates activation of protein kinase C (PKC) through direct binding and activation of phospholipase C-gamma (PLC-gamma), and has also been shown to activate the cytoplasmic tyrosine kinase Src. Treatment of the cells with the PKC inhibitor bisindolylmaleimide does not prevent tube formation. In contrast, Src kinase activity is a prerequisite for EC differentiation, since treatment of the cells with PP1, a Src family specific inhibitor, abrogates tube formation. In differentiating EC, FGF-2 induces complex formation between Src and focal adhesion kinase (FAK). These data indicate that the Ras pathway is initiated via Shc or FRS2, dependent on the cellular program. Blocking the function of Src family kinases, attenuates differentiation.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Animals, Calcium-Calmodulin-Dependent Protein Kinases, Cell Adhesion Molecules, Cell Differentiation, Cell Division, Cell Line, Endothelium, Vascular, Enzyme Inhibitors, Fibroblast Growth Factor 2, Flavonoids, Focal Adhesion Kinase 1, Focal Adhesion Protein-Tyrosine Kinases, GRB2 Adaptor Protein, Genes, ras, Indoles, Isoenzymes, Maleimides, Membrane Proteins, Mice, Mice, Transgenic, Phospholipase C gamma, Phosphoproteins, Platelet-Derived Growth Factor, Protein Kinase C, Protein-Tyrosine Kinases, Proteins, Proto-Oncogene Proteins c-sis, Receptor Protein-Tyrosine Kinases, Receptor, Fibroblast Growth Factor, Type 1, Receptors, Fibroblast Growth Factor, Recombinant Proteins, Signal Transduction, Type C Phospholipases, ras Proteins, src Homology Domains
Adaptor Proteins, Signal Transducing, Animals, Calcium-Calmodulin-Dependent Protein Kinases, Cell Adhesion Molecules, Cell Differentiation, Cell Division, Cell Line, Endothelium, Vascular, Enzyme Inhibitors, Fibroblast Growth Factor 2, Flavonoids, Focal Adhesion Kinase 1, Focal Adhesion Protein-Tyrosine Kinases, GRB2 Adaptor Protein, Genes, ras, Indoles, Isoenzymes, Maleimides, Membrane Proteins, Mice, Mice, Transgenic, Phospholipase C gamma, Phosphoproteins, Platelet-Derived Growth Factor, Protein Kinase C, Protein-Tyrosine Kinases, Proteins, Proto-Oncogene Proteins c-sis, Receptor Protein-Tyrosine Kinases, Receptor, Fibroblast Growth Factor, Type 1, Receptors, Fibroblast Growth Factor, Recombinant Proteins, Signal Transduction, Type C Phospholipases, ras Proteins, src Homology Domains
Oncogene
Date: Jun. 03, 1999
PubMed ID: 10362356
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