Role of tyrosine residues and protein interaction domains of SHC adaptor in VEGF receptor 3 signaling.
The VEGFR3/FLT4 receptor, which is involved in vasculogenesis and angiogenesis, binds and phosphorylates SHC proteins on tyrosine residues. SHC contains two phosphotyrosine interaction domains: a PTB (Phosphotyrosine Binding) and a SH2 (Src Homology 2) domain. Previous studies have shown that SHC proteins are phosphorylated on Y239/Y240 and Y313 (Y317 in ... humans) by tyrosine kinases such as the EGF and IL3 receptors. We have investigated which of the SHC tyrosine residues are targeted by the VEGFR3/ FLT4 kinase and the role of the SHC PTB and SH2 domains in this process. Our results show that Y239/ Y240 and Y313 are simultaneously phosphorylated by the kinase, creating GRB2 binding sites. Mutation of SHC PTB, but not SH2, domain interferes with the SHC phosphorylation by VEGFR3/FLT4. Soft agar assay experiments revealed that the VEGFR3/FLT4 transforming capacity is increased by the mutation of Y239/Y240 to phenylalanines in SHC, suggesting that these two residues mediate an inhibitory signal for cell growth. Mutation of the two phosphorylation sites increases this effect, suggesting that they have a synergistic role.
Mesh Terms:
Cell Line, Cell Transformation, Viral, Humans, Kinetics, Mutagenesis, Phosphorylation, Protein Binding, Receptor Protein-Tyrosine Kinases, Receptors, Cell Surface, Retroviridae, Signal Transduction, Tyrosine, Vascular Endothelial Growth Factor Receptor-3
Cell Line, Cell Transformation, Viral, Humans, Kinetics, Mutagenesis, Phosphorylation, Protein Binding, Receptor Protein-Tyrosine Kinases, Receptors, Cell Surface, Retroviridae, Signal Transduction, Tyrosine, Vascular Endothelial Growth Factor Receptor-3
Oncogene
Date: Jan. 14, 1999
PubMed ID: 9927207
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