Details

Autor(en) / Beteiligte

• FOURNIER, E
• BLAIKIE, P
• ROSNET, O
• MARGOLIS, B
• BIRNBAUM, D
• BORG, J.-P

Titel

Role of tyrosine residues and protein interaction domains of SHC adaptor in VEGF receptor 3 signaling

Ist Teil von

• Oncogene, 1999-01, Vol.18 (2), p.507-514

Ort / Verlag

Basingstoke: Nature Publishing

Erscheinungsjahr

1999

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.