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

Oncogene volume 18, pages 507–514 (1999)Cite this article

Abstract

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.

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Abbreviations

CSF1:

Colony Stimulating Factor 1

FLT4:

FMS-Like Tyrosine kinase 4

GRB2:

Growth factor Receptor Bound protein 2

PTB:

Phosphotyrosine Binding

PY:

Phosphotyrosine

RTK:

Receptor Tyrosine Kinase

SH2:

SRC Homology domain 2

SHC:

SRC Homology and Collagen

SOS:

Son of Sevenless

VEGF:

Vascular Endothelial Growth Factor

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Acknowledgements

This work was supported by INSERM, La Ligue Nationale Contre le Cancer (axe oncogenèse) and the Howard Hughes Medical Institute.

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Author notes

  1. Pamela Blaikie

    Present address: Memorial Sloan Kettering Cancer Center, New York, USA

  2. Olivier Rosnet

    Present address: Centre d'Immunologie de Marseille, France

Authors and Affiliations

  1. Molecular Oncology Laboratory, INSERM U.119, Marseille, France

    Emmanuel Fournier, Olivier Rosnet, Daniel Birnbaum & Jean-Paul Borg

  2. Department of Internal Medicine and Biological Chemistry and the Howard Hughes Medical Institute, Ann Arbor, Michigan, USA

    Pamela Blaikie, Benjamin Margolis & Jean-Paul Borg

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Fournier, E., Blaikie, P., Rosnet, O. et al. Role of tyrosine residues and protein interaction domains of SHC adaptor in VEGF Receptor 3 signaling. Oncogene 18, 507–514 (1999). https://doi.org/10.1038/sj.onc.1202315

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